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  • pharmacokinetics  (114)
  • Springer  (114)
  • 2020-2024
  • 1995-1999  (114)
  • 1985-1989
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  • 1995  (76)
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  • 2020-2024
  • 1995-1999  (114)
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  • 1
    Electronic Resource
    Electronic Resource
    Methotrexate in juvenile rheumatoid arthritis (1995)
    Springer
    European journal of clinical pharmacology 47 (1995), S. 507-511 
    Details
    ISSN: 1432-1041
    Keywords: Methotrexate ; Juvenile rheumatoid arthritis ; pharmacokinetics ; age dependence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Children with juvenile rheumatoid arthritis (JRA) have been reported to require higher doses (per kg body weight) of methotrexate (MTX) than adults with rheumatoid arthritis to control their disease. The purpose of the present study was to characterise the plasma pharmacokinetics of MTX and its major metabolite, 7-hydroxymethotrexate (7-OHMTX) in children, and to compare the results with those previously obtained in adults. Thirteen patients (age 5–16 y) with JRA (median disease duration 5.5 y) were studied after once weekly oral administration of MTX (median 0.21 mg·kg−1). The analytical method was sufficiently sensitive to permit determination of plasma and urinary concentrations of MTX and 7-OHMTX during the entire dose interval in most of the patients. The dose normalized area under the plasma concentration versus time-curve (AUC) of MTX increased with the age of the children and was lower than previously found in adults. The dose normalized AUC of 7-OHMTX was not dependent on age. No correlation was found between the AUCs of MTX and 7-OHMTX. The results suggest that the age-dependence of the pharmacokinetics of MTX might explain the observation that at least some children require higher doses of MTX than adults to obtain a sufficient therapeutic effect.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00193703
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  • 2
    Electronic Resource
    Electronic Resource
    Antipyrine disposition in obesity: evidence for negligible effect of obesity on hepatic oxidative metabolism (1995)
    Springer
    European journal of clinical pharmacology 47 (1995), S. 525-530 
    Details
    ISSN: 1432-1041
    Keywords: Antipyrine disposition ; Obesity ; pharmacokinetics ; oxidative metabolism ; weight reduction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Following an overnight fast and 2 days of abstention from caffeine, a single 1.0-g oral dose of antipyrine was administered to 20 obese but otherwise healthy subjects (group A) and 11 healthy volunteers (group B). Weight, Body Mass Index (BMI) and % of Ideal Body Weight (IBW) were significantly greater in the obese than in the lean group. (Mean 110.4 vs 62.7 kg; 38.5 vs 22.3 kg · m−2 and 181vs 106 % respectively). In a subgroup of 6 obese subjects (group C) antipyrine was given again 11.3 months later after a 29.8 kg mean weight loss. Antipyrine apparent volume of distribution (V) and elimination half-life (t 1/2) were significantly greater in the obese than in the lean group (V 49.9 vs 34.3 l respectively; t 1/2 15.5 vs 12.0 h respectively), but its clearance rate (CLo) values were similar. V corrected for total body weight was significantly reduced in group A than in group B (0.45 vs 0.55 l · kg−1 respectively). Stratified comparison of antipyrine pharmacokinetics between obese and lean subjects according to age, gender and smoking habits did not alter the overall results. In group C, weight reduction was associated with a significant decrease in antipyrine V (from 51.8 to 47.5 l) and t 1/2 (from 15.1 to 12.7 h), and a non-significant increase in antipyrine CLo. We conclude that in severely obese subjects, antipyrine total V is mildly increased but V corrected for total body weight is significantly decreased. In addition, obesity is associated with a slight prolongation of antipyrine t 1/2 whereas its CLo is unaltered. These findings may indicate that obesity, even in its extreme form, has a negligible effect on the oxidative metabolic capacity of the liver.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00193706
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  • 3
    Electronic Resource
    Electronic Resource
    Oral bioavailability of CHF1194, an inclusion complex of piroxicam and β-cyclodextrin, in healthy subjects under single dose and steady-state conditions (1995)
    Springer
    European journal of clinical pharmacology 47 (1995), S. 531-536 
    Details
    ISSN: 1432-1041
    Keywords: Piroxicam ; β-Cyclodextrin ; pharmacokinetics ; healthy volunteers ; multiple dose ; adverse event
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract CHF1194 is an inclusion complex of β-cyclodextrin with the nonsteroidal anti-inflammatory drug piroxicam. In man, β-cyclodextrin acts as a carrier of piroxicam. As the inclusion complex of piroxicam-β-cyclodextrin is wettable and more water soluble, the absorption rate of the drug is increased whilst its other pharmacokinetic characteristics remain unchanged. The aim of the present study in 12 healthy subjects was to compare the oral bioavailability of 20 mg piroxicam in a CHF1194 tablet and a plain piroxicam capsule after a single dose and after two weeks of once daily administration, and also to assess the plasma levels and urinary excretion of β-cyclodextrin after CHF1194 administration. The two treatments were administered in cross-over fashion, separated by a wash-out period of three weeks. Piroxicam, 5′-hydroxypiroxicam and β-cyclodextrin were monitored in plasma and urine for 120 h after the first and last doses. Clinical tolerance was excellent and no adverse event occurred during either phase of the study. The extent of absorption of piroxicam from the CHF1194 tablet after the single dose was equivalent to that after the plain piroxicam capsule, within confidence limits of less than 80–125%. After repeated dosing, CHF1194 yielded the same steady-state systemic concentrations of piroxicam and 5′-hydroxypiroxicam as the reference capsule, and similar excretion pattern of the metabolite. After both single and multiple dosing, piroxicam was absorbed more rapidly after CHF1194, an expected consequence of the complexation of piroxicam with β-cyclodextrin. This may be of therapeutic interest as it might accelerate the onset of pain relief. The pharmacokinetics of piroxicam was linear after the doses used here, suggesting that long term treatment with CHF1194 should not require any change in dosing regimen. Even after 14 days of repeated administration of CHF1194, β-cyclodextrin could not be detected in plasma or urine, suggesting that in man the unchanged oligosaccharide was absorbed to a very small extent.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00193707
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  • 4
    Electronic Resource
    Electronic Resource
    Furosemide disposition in patients on CAPD (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 385-390 
    Details
    ISSN: 1432-1041
    Keywords: Furosemide ; Dialysis ; continuous ambulatory peritoneal ; drug disposition ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Single doses of oral and intravenous furosemide were given to 8 healthy male volunteers (40 mg) and 11 patients with renal failure maintained on continuous ambulatory peritoneal dialysis (CAPD) (80 mg). In the volunteers, absorption was variable. Only one half of the intravenous dose and one third of the oral dose was available for renal pharmacological action as judged by the urinary recovery. In the patients, absorption was also variable and was markedly delayed (t max 128 vs 90 min) but more complete (bioavailability 70.1 vs 53.6%). The differences between the two groups were not significant, however (95% C.I.: -90 to 30 and -40.4 to 7.5 respectively). The mean elimination half-life was significantly longer in the patients following both the oral (228 vs 65.1 min) and intravenous dose (195 vs 60.3 min). The total body clearance of furosemide in the volunteers was 138 ml·min−1 and this was much lower in the CAPD patients (61.9 ml·min−1) in whom the renal clearance was minimal. The peritoneal clearance of furosemide was negligible. Although there were trends indicating differences in absorption between the two groups, the significant differences in furosemide disposition observed in CAPD patients were due to renal failure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194955
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  • 5
    Electronic Resource
    Electronic Resource
    Effects of altitude (4300 M) on the pharmacokinetics of caffeine and cardio-green in humans (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 167-170 
    Details
    ISSN: 1432-1041
    Keywords: Caffeine ; Cardio-green ; Indocyanine Green ; altitude ; metabolism ; pharmacokinetics ; hypoxia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The effects of chronic exposure to high altitude on the pharmacokinetics of caffeine and cardiogreen (ICG) were examined in eight healthy males (23–35 y) at sea level (SEA) and following 16 days residence at 4300 m (ALT). ICG (0.5 mg · kg−1) was administered as an intravenous bolus and caffeine (4 mg · kg−1) in an orally ingested solution. The concentration of ICG, caffeine, and the primary metabolites of caffeine (MET) were determined in serial blood samples and their pharmacokinetics computed. In comparison to SEA, ALT resulted in a significant decrease in the caffeine half-life (t1/2, 4.7 vs 6.7 h) and area under the curve (2.5 vs 3.7 g · 1−1 · min−1), and increased clearance (117 vs 86 ml · min−1 · 70 kg−1). In ALT the area under the curve of ICG significantly decreased (85 vs 207 mg · 1−1 · min−1) and the volume of distribution and clearance increased (5.2 vs 2.41 and 532 vs 234 ml · min−1 respectively) compared to SEA. There was a significant increase in the AUC ratio of MET to caffeine indicating that either metabolite formation or elimination was increased in ALT. These results demonstrate that in humans, chronic exposure to 4300 m results in the modification of the pharmacokinetics of caffeine and ICG.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00192744
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  • 6
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and bioavailability of a sustained-release diltiazem formulation (Mono-Tildiem LP 300 mg) after repeated administration in healthy volunteers (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 259-264 
    Details
    ISSN: 1432-1041
    Keywords: Diltiazem ; sustained-release formulation ; pharmacokinetics ; bioavailability ; bioequivalence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The usual dosage regimen of diltiazem (Tildiem) is 60 mg 3–4 times a day. A sustained-release formulation has been developed (Mono-Tildiem LP 300 mg) in order to allow a single daily administration. Two repeated dosing studies were performed in healthy volunteers. The absolute bioavailability of sustained-release diltiazem LP 300 mg was investigated using concomitant i.v. administration of 13C-labelled drug: absolute bioavailability of the “once a day” formulation was 35%. The second study compared sustained-release diltiazem LP 300 mg with the standard formulation of diltiazem. The results showed that the diltiazem plasma concentrations obtained after the LP formulation remained stable between 2 and 14 h after administration and were compatible with a once a day administration. Relative bioavailability of sustained-release diltiazem LP 300 mg was 79.3% compared with diltiazem. Therefore, a unitary dose of sustained-release diltiazem LP 300 mg was chosen as the dose equivalent to the daily dose administered with the standard diltiazem formulation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00198308
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  • 7
    Electronic Resource
    Electronic Resource
    Disposition of lorazepam in diabetes: differences between patients treated with beef/pork and human insulins (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 253-258 
    Details
    ISSN: 1432-1041
    Keywords: Diabetes ; Human insulin ; Lorazepam ; pharmacokinetics ; glucuronidation ; enterohepatic circulation ; animal insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics of lorazepam was examined in 10 male patients with insulin-dependent diabetes mellitus before and following treatment with neomycin and cholestyramine. Neomycin and cholestyramine were given in an attempt to block the enterohepatic circulation of lorazepam and so to permit an in vivo estimate of hepatic glucuronidation. The volume of distribution and clearance of free lorazepam in diabetic patients were not significantly different from the corresponding estimates in 14 normal controls. Neomycin and cholestyramine increased the clearance of lorazepam by 63% consistent with their effect in non-diabetic controls. However, patients on beef/pork insulin exhibited a greater than normal increase on this interupting regimen (125%), and had a significantly greater neomycin/cholestyramine cycling-interrupted clearance of lorazepam than either normal controls or patients on human insulin (15.4 vs. 6.96 and 7.87 ml·min−1·kg−1). The clearance was correlated positively and significantly with HbA1c and glycated proteins (fructosamine), but only in patients on human insulin. Thus, the pharmacokinetics of lorazepam was not altered in patients with insulin-dependent diabetes mellitus. However, it is possible that there are differences in the rate and extent of hepatic glucuronidation and enterohepatic circulation of lorazepam between patients treated with beef/pork and human insulins and between diabetics treated with beef/pork insulin and non-diabetic controls.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00198307
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  • 8
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of 5-aminosalicylic acid from controlled-release capsules in man (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 273-277 
    Details
    ISSN: 1432-1041
    Keywords: Mesalamine ; 5-aminosalicylic acid ; controlled release capsules ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract One gram single dose of Pentasa controlled-release capsules was administered to 24 healthy volunteers under fasting condition. Mean plasma 5-aminosalicylic acid (5-ASA) and acetyl 5-ASA concentrations peaked at 0.53 μg · ml−1 and 1.33 μg · ml−1 from 3 to 4 hours following dosing, respectively. The half-lives of both compounds could not be determined as absorption of 5-ASA was continuous throughout the gastrointestinal tract. An average of 29.4% (CV: 27%) of the dose was excreted in the urine primarily as acetyl 5-ASA. Up to 91.1% of the dose was released from the capsules. Forty percent of the dose (CV: 40%) was eliminated in the feces, with 8.9% of the dose remained as formulation bounded 5-ASA, indicating that controlled-release capsules continue to release drug throughout the GI tract. 5-ASA contributed 46.7% of the salicylates eliminated in the feces and acetyl 5-ASA accounted for the balance. Controlled-release capsules produced three times more total salicylates and 10 times more total and free 5-ASA in the feces than did 5-ASA suspension. Thus, while lower systemic levels of salicylates were absorbed, greater therapeutic quantities of 5-ASA were available in the bowel.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00198311
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  • 9
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of thiopental after single and multiple intravenous doses in critical care patients (1995)
    Springer
    European journal of clinical pharmacology 49 (1995), S. 127-137 
    Details
    ISSN: 1432-1041
    Keywords: Thiopental ; Pharmacokinetic modelling ; pharmacokinetics ; single dose ; multiple dosing ; neurosurgical patients ; variability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Thiopental was administered to neurosurgical patients for cerebral protection and its pharmacokinetic parameters were determined after a single bolus of 540, 1000 or 1500 mg (3 subjects) or after multiple doses of 250 mg (5 subjects) and 500 mg (2 subjects) every two hours for up to 7 days. The data were analysed by a two- or three- compartment model and linear kinetics. After a single IV bolus, the mean initial volume of distribution (V1) was 0.4811·kg−1, and the steady-state volume of distribution (Vss) was 2.16 1·kg−1. The distribution (t1/2α) and elimination (t1/2β) half-lives were 0.590 and 5.89 h, respectively, and the mean residence time (MRT) was 7.44 h. The clearance was 5.41 ml·min−1·kg−1. With repeated injections, the pharmacokinetic parameters for each patient were estimated taking into account all administered doses and blood samples, which were taken whenever possible daily at steady state and after the last dose. The variability observed in the pharmacokinetic parameters of thiopental reflected by the coefficient of variation (CV%) was wide but was of similar magnitude within patients (CVintra) as it was between patients (CVinter). The steady-state trough plasma concentration (Cmin obs) ranged from 4.8 to 30 mg·1−1 (mean 16.0 mg·1−1 and median 14.3 mg·1−1). Peak concentrations (Cmax obs) ranged from 8.35 to 45 mg·1−1 (25.4 mg·1−1, and median 23.3 mg·1−1). The values of V1 and Vss were similar to those obtained after a single dose. For V1, the mean was 0.333 1·kg−1. The mean Vss was 2.68 1·kg−1, with a CVintra of 12.6 to 56% and a CVinter of 13.2%. A shorter distribution half-life t1/2α was noted on multiple dosing; the mean value was 0.122 h. The elimination half-life t1/2β and the mean residence time became longer due to a decrease in clearance. For t1/2β the mean value was 16.3 h. The mean MRT was 21.9 h, CVintra 9.19 to 48.5%, and the CVinter 35.3%. The mean clearance was 2.16 ml·min−1·kg−1, CVintra 7.28 to 25.5%, and the CVinter 20.4%. This value is 50% lower than after a single dose. Identification of the kinetic parameters of thiopental allows simulation of the effects of doses on subsequent plasma levels and will permit a priori prediction of day to day adjustment of drug dosage.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00192371
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  • 10
    Electronic Resource
    Electronic Resource
    Limitations of the maximum entropy principle in devising drug input rate (1995)
    Springer
    European journal of clinical pharmacology 49 (1995), S. 139-143 
    Details
    ISSN: 1432-1041
    Keywords: Intestinal absorption ; Amoxicillin ; pharmacokinetics ; maximum entropy ; input rate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract A computer program applying the principle of maximum entropy to the analysis of drug absorption rate has been developed. Plasma concentrations of amoxicillin obtained after oral and intravenous dosing have been analysed, together with simulated data corresponding to a complex input. Amoxicillin absorption rates devised by the program were similar to those obtained by a standard deconvolution method, although they were displayed as an almost continuous profile. However, improbable fluctuations were obtained with some data sets and the fraction absorbed was underestimated by 13%. With the simulated data, the maximum entropy program did not provide a better solution than the standard deconvolution procedure, and it was sensitive to the addition of random error and to the number of samples. The maximum entropy principle, as implemented in our computer program, may not have a better performance than standard deconvolution procedures, especially in human experiments where the number of blood samples is usually limited.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00192372
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  • 11
    Electronic Resource
    Electronic Resource
    Single dose pharmacokinetics of sumatriptan in healthy volunteers (1995)
    Springer
    European journal of clinical pharmacology 47 (1995), S. 543-548 
    Details
    ISSN: 1432-1041
    Keywords: Sumatriptan ; pharmacokinetics ; single dose ; bioavailability ; dose proportionality ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Sumatriptan is classified as a vascular 5HT1 receptor agonist and is effective in the acute treatment of migraine and cluster headache. Sumatriptan is available as an injection for subcutaneous administration and as a tablet for oral administration. The pharmacokinetics of sumatriptan differ depending on the route of administration. The mean subcutaneous bioavilability is 96% compared to 14% for the oral tablet. The lower bioavailability following oral administration is due mainly to presystemic metabolism. The inter-subject variability in plasma sumatriptan concentrations is greater following oral administration and a faster rate of absorption of drug into the systemic circulation is achieved following subcutaneous dosing. The pharmacokinetics of sumatriptan are linear up to a subcutaneous dose of 16 mg. Following oral dosing up to 400 mg, the pharmacokinetics are also linear, with the exception of rate of absorption, as indicated by a dose dependent increase in time to peak concentration. Sumatriptan is a highly cleared compound that is eliminated from the body primarily by metabolism to the pharmacologically inactive indoleacetic acid analogue. Both sumatriptan and its metabolite are excreted in the urine. Although the renal clearance of sumatriptan is only 20% of the total clearance, it exceeds the glomerular filtration rate, indicating that sumatriptan undergoes active renal tubular secretion. Sumatriptan has a large apparent volume of distribution (170 1) and an elimination half-life of 2 h. Oral doses of sumatriptan were administered as a solution of dispersible tablets and subcutaneous dosing was by injection into the arm. In clinical practice, sumatriptan is administered as a film coated tablet or by subcutaneous injection into the thigh.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00193709
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  • 12
    Electronic Resource
    Electronic Resource
    The pharmacokinetics of granisetron, a 5-HT3 antagonist in healthy young and elderly volunteers (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 519-520 
    Details
    ISSN: 1432-1041
    Keywords: Granisetron ; pharmacokinetics ; elderly ; tolerance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194344
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  • 13
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamics of a single dose of recombinant human growth hormone after subcutaneous administration by jet-injection: comparison with conventional needle-injection (1995)
    Springer
    European journal of clinical pharmacology 49 (1995), S. 69-72 
    Details
    ISSN: 1432-1041
    Keywords: Growth hormone ; Jet-injection ; pharmacokinetics ; pharmacodynamics ; Somatomedin C ; free fatty acids
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics and pharmacodynamics of recombinant human growth hormone (rhGH) were studied after a single subcutaneous dose given by jet-injection, and have been compared with the results obtained after conventional needle-injection. Twelve healthy male volunteers completed an open label, randomised, two-way crossover study, with a 7-day washout period between the two single sc doses. Pharmacokinetic parameters were derived from rhGH concentrations in blood samples collected regularly over 24 h after dosing on Day 1 of each period. To investigate the pharmacodynamics, additional samples were taken for the analysis of somatomedin C (IGF-I) and free fatty acids (FFA). A higher and earlier Cmax was found after jet-injection (ratio (%) jet-injected/needle-injected 124; 90%-confidence interval 108 – 142). The AUC0−∞ for rhGH were similar (ratio (%) jet-injected/needle-injected 98; 90%-confidence interval 93 – 103). Both treatments were associated with a significant and similar rise in IGF-I. Both administrations of rhGH were associated with identical rhythmical changes in FFA. The study indicates that jet-injected and needle-injected rhGH are bioequivalent with respect to the amount absorbed. The criterion for bioequivalence is not met for the rate of absorption. It is unlikely that the latter finding will influence the pharmacodynamics of rhGH, since bioequipotency was established for the effect on IGF-I generation. Jet-injection was safe in use and was generally well tolerated.
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    URL: http://dx.doi.org/10.1007/BF00192361
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  • 14
    Electronic Resource
    Electronic Resource
    Effects of cimetidine on pharmacokinetics and pharmacodynamics of losartan, an AT1-selective non-peptide angiotensin II receptor antagonist (1995)
    Springer
    European journal of clinical pharmacology 49 (1995), S. 115-119 
    Details
    ISSN: 1432-1041
    Keywords: Losartan ; Cimetidine ; pharmacokinetics ; plasma renin activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract This was a 2-period randomized, crossover study in 8 healthy males to determine the effects of cimetidine (400 mg q.i.d. for 6 days) on the pharmacokinetics and pharmacodynamic effects of the angiotensin II receptor antagonist, losartan (100 mg). Cimetidine increased the AUC for losartan 18% without affecting the AUC for E-3174, the active metabolite of losartan. The increase in plasma renin activity following losartan was not affected by cimetidine (maximum mean increases 12.6 and 12.1 ng Ang I·ml−1·h−1 without and with cimetidine, respectively). These results indicate that cimetidine does not appear to alter the pharmacokinetics or pharmacodynamics of losartan to a clinically significant extent.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00192369
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  • 15
    Electronic Resource
    Electronic Resource
    Lack of relationship between quinidine pharmacokinetics and the sparteine oxidation polymorphism (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 501-504 
    Details
    ISSN: 1432-1041
    Keywords: Quinidine ; CYP2D6 ; Sparteine oxidation polymorphism ; (3S)-3OH-quinidine ; quinidine-N-oxide ; dihydroquinidine ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Quinidine is a very potent inhibitor of CYP2D6, but the role of the enzyme in the biotransformation of quinidine has only been investigated in a single in vitro study and in two small in vivo experiments, with contradictory results. The present investigation was designed to present definite evaluation of whether quinidine is metabolised by CYP2D6. Eight poor metabolizers (PM) and 8 extensive metabolizers (EM) of sparteine each took one oral dose of 200 mg quinidine. In the EM, the total clearance, the clearance via 3-hydroxylation and the clearance via N-oxidation, were 33, 3.7 and 0.23 l·h−1, respectively. In the PM, the corresponding values were 29, 3.1 and 0.18 l·h−1, respectively. There were no statistically significant differences between EM and PM in any of these pharmacokinetic parameters. It is concluded that CYP2D6 is not an important enzyme for the oxidation of quinidine.
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    URL: http://dx.doi.org/10.1007/BF00194341
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  • 16
    Electronic Resource
    Electronic Resource
    Single-dose pharmacokinetics of nefazodone in healthy young and elderly subjects and in subjects with renal or hepatic impairment (1995)
    Springer
    European journal of clinical pharmacology 49 (1995), S. 221-228 
    Details
    ISSN: 1432-1041
    Keywords: Nefazodone ; Geriatric assessment ; Hepatic cirrhosis ; Renal impairment ; pharmacokinetics ; antidepressive agents
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The single-dose pharmacokinetics of nefazodone (NEF) and its metabolites hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) were examined in 12 healthy younger subjects ≤55 years of age (YNG), 12 elderly subjects ≥65 years of age (ELD), 12 patients with biopsy proven hepatic cirrhosis (HEP) and 12 patients with moderate renal impairment (REN), ClCR 20–60 ml·min−1. The study was of parallel group design, with each of the four subject groups receiving escalating single oral doses of 50, 100 and 200 mg of nefazodone at 1 week intervals. Serial blood samples for pharmacokinetic analysis were collected for 48 h following each dose and plasma samples were assayed for NEF, HO-NEF and mCPP by a validated HPLC method. Single oral doses up to 200 mg of nefazodone were well tolerated by all subjects. Maximum plasma levels of NEF and HO-NEF were generally attained within 1 h after administration of nefazodone. HO-NEF and mCPP plasma levels were about 1/3 and 〈1/10 those of NEF, respectively. There were no apparent gender-related pharmacokinetic differences in any group of subjects. NEF and HO-NEF pharmacokinetics were dose dependent in all four subject groups; a superproportional increase in AUC and an increase in t1/2 with increasing dose was obtained, indicative of nonlinear pharmacokinetics. Relative to normal subjects, elderly and cirrhotic subjects exhibited increased systemic exposure to NEF and HO-NEF, as reflected by AUC, at all doses of nefazodone; subjects with moderate renal impairment did not. Elderly and cirrhotic patients may require lower doses of NEF to achieve and maintain therapeutic effectiveness.
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    URL: http://dx.doi.org/10.1007/BF00192383
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  • 17
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    Steady-state pharmacokinetics of nefazodone in subjects with normal and impaired renal function (1995)
    Springer
    European journal of clinical pharmacology 49 (1995), S. 229-235 
    Details
    ISSN: 1432-1041
    Keywords: Nefazodone ; Renal impairment ; pharmacokinetics ; antidepressive agents
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The steady-state pharmacokinetics of nefazodone (NEF) and its metabolites hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) were compared in subjects with normal and impaired renal function. Patients: The Study was of parallel group design which included 7 subjects with normal (NOR) renal function, CLCR≥72 ml·min−1·1.73 m−2, 6 with moderate (MOD) renal impairment, CLCR 31–60 ml·min−1·1.73 m−2 and 9 with severe (SEV) renal impairment, CLCR≤30 ml·min−1·1.73 m−2. Subjects in each renal function group received a 100-mg oral dose of nefazodone hydrochloride BID for 7 days and a single morning dose on day 8. Starting 48 h after the last 100-mg dose, 200-mg doses were administered on a similar schedule to 3, 4 and 3 subjects from each renal function group (NOR, MOD and SEV, respectively). Single trough blood samples just prior to each morning dose (Cmin) and serial samples after the dose on day 8 were obtained at each dose level for pharmacokinetic analysis. Plasma samples were assayed by a specific HPLC method for NEF, HO-NEF and mCPP. The CMIN data indicated that steady state was attained by the third day of BID administration of both the 100- and 200-mg doses of nefazodone, regardless of degree of renal function. Both NEF and HO-NEF attained steady-state Cmax within 2 h after administration of nefazodone; tmax for mCPP was less defined and more delayed. HO-NEF and mCPP plasma levels were about 1/3 and 〈1/10 those of NEF, respectively, regardless of the status of renal function. Steady-state systemic exposure of NEF and HO-NEF, as reflected by AUC and Cmax, and elimination t1/2 values did not differ significantly among renal function groups. Conclusion: The study results suggest that dose adjustments may not be necessary, but nefazodone should be used with caution in the presence of severe renal impairment.
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    URL: http://dx.doi.org/10.1007/BF00192384
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    Relationship of changes in felodipine pharmacokinetics to haemodynamics during chronic oral treatment of congestive heart failure patients (1995)
    Springer
    European journal of clinical pharmacology 49 (1995), S. 203-210 
    Details
    ISSN: 1432-1041
    Keywords: Felodipine ; pharmacokinetics ; haemodynamics ; congestive heart failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract In congestive heart failure patients the kinetics of felodipine, a dihydropyridine calcium antagonist, show interpatient differences after acute i.v. administration that disappear after 8 weeks oral treatment with a change in kinetics in the patients with the largest clearances (CL) and the smallest volumes of distribution (V SS). Pharmacokinetic and haemodynamic data were combined to construct a haemodynamic-pharmacokinetic model. This model shows that the differences between the patients in i.v. pharmacokinetics are consistent with a difference in plasma flow distribution between liver and poorly perfused tissues. In patients in whom kinetics changed, felodipine treatment is supposed to cause a redistribution of flow from liver to peripheral tissues, accompanied by a decreased work load of the heart and a larger increase in VO2max during therapy than in the other patients, whose workload increased. This suggests a better therapeutic response in the patients whose kinetics changed. As change in kinetics is related to felodipine CL and CL to liver plasma flow, felodipine CL or even indocyanine CL might be predictive for the therapeutic effect of felodipine.
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    URL: http://dx.doi.org/10.1007/BF00192380
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  • 19
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    The tolerability, pharmacokinetics and lack of effect on plasma cholesterol of 447C88, an AcylCoA:Cholesterol Acyl Transferase (ACAT) inhibitor with low bioavailability, in healthy volunteers (1995)
    Springer
    European journal of clinical pharmacology 49 (1995), S. 243-249 
    Details
    ISSN: 1432-1041
    Keywords: Cholesterol acyltransferase ; Hypocholesterolaemic ; 447C88 ; volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract 447C88 (N-Heptyl-N′-(2,4 difluoro-4-6-(2(-4-(2,2 dimethylpropyl)phenyl)ethyl)phenyl)urea) is an inhibitor of human microsomal AcylCoA:Cholesterol acyltransferase (ACAT) with an IC50 of 10.2 ng·ml−1 (23 nM). It is poorly absorbed but 5 mg·kg−1·day−1 completely abolishes the rise in plasma cholesterol in cholesterol-fed rats. In this study, twelve healthy, male volunteers received single, oral doses of 25, 50, 100, 200, 400 and 800 mg of 447C88 (n+8) or placebo (n+4) with food in a double-blind study with at least a week between occasions. The 400 mg dose was repeated after an overnight fast. Subsequently, fourteen different volunteers received a single 200 mg dose of 447C88 (n+8) or placebo (n+6) with food and, a week later, the same dose twice daily for 10 days; all doses were given with food. All doses were well tolerated with no significant changes in vital signs, full blood counts or plasma biochemical profiles. Plasma concentrations of 447C88 were unquantifiable after the fasting dose and low after all other doses. Mean Cmax and AUC were 1.8 ng·ml−1 and 9.0 ng·ml−1·h after 200 mg rising to 5.4 ng·ml−1 and 23.8 ng·ml−1·h respectively after 800 mg; t1/2 was 1.3 to 5.2 h. After 10 days dosing, plasma 447C88 concentrations were higher in the evening than the morning probably due to administration of the evening dose with more food. There were no significant changes in plasma triglcerides or total, LDL- or HDL-cholesterol after dosing with 447C88.
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  • 20
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    Whole-blood pharmacokinetics and metabolic effects of the topical carbonic anhydrase inhibitor dorzolamide (1995)
    Springer
    European journal of clinical pharmacology 47 (1995), S. 453-460 
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    ISSN: 1432-1041
    Keywords: Dorzolamide ; Glaucoma ; carbonic anhydrase ; pharmacokinetics ; renal effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Following a single-dose, open-label, pilot pharmacokinetic study in six subjects, the systemic pharmacokinetics and metabolic effects of dorzolamide after topical ocular administration were investigated in a double-blind, randomised, placebo-controlled study in 12 healthy volunteers. The subjects received a controlled diet on the 5 days before treatment initiation and throughout the study. For 14 days, a bilateral q.i.d. regimen of 3% dorzolamide, consisting of approximately 7.7 μg per day (21.3 μmol) dorzolamide hydrochloride, or placebo was given. Blood and urine electrolytes and acid-base profiles were measured 1 day prior to treatment and on days 1, 7 and 14 of treatment, and 24-h urine samples were collected daily. Topically applied dorzolamide was slowly taken up in erythrocytes and eliminated with a half life of approximately 120 days. Compared to the pre-study values, no significant treatment effect was observed in either the daily profiles or the 14-day cumulative sodium, potassium and citrate excretions. Two other volunteers given acetazolamide (125 mg q.i.d.) and assessed with the identical set of observations demonstrated marked metabolic changes. In spite of the prolonged and marked inhibition of carbonic anhydrase in red blood cells by dorzolamide, clinically significant metabolic and renal effects were not observed. The ocular tolerability profile was acceptable to all subjects.
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    URL: http://dx.doi.org/10.1007/BF00196861
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  • 21
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    Elimination of amrinone during continuous veno-venous haemofiltration after cardiac surgery (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 57-59 
    Details
    ISSN: 1432-1041
    Keywords: Amrinone ; continuous veno-venous haemofiltration ; drug monitoring ; pharmacokinetics ; low cardiac output syndrom ; elimination ; renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract We studied the elimination of amrinone during continuous veno-venous haemofiltration (CVVHF) in three anuric patients after cardiac surgery. The patients had developed low cardiac output followed by acute prerenal failure. Plasma amrinone levels measured by HPLC were fitted to a two-compartment model. We found significant amrinone clearance, with a mean sieving coefficient (S) of 0.44%, which correlates with the protein-unbound, pharmacologically effective fraction of amrinone. The AUC of the arterial plasma concentration-time curve was decreased by 49.8%. All pharmacokinetic parameters showed wide interindividual variation. To ensure the therapeutic effect of amrinone and to avoid toxic adverse effects monitoring of plasma amrinone levels is necessary.
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    URL: http://dx.doi.org/10.1007/BF00202173
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  • 22
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    Paracetamol disposition in Thai patients during and after treatment of falciparum malaria (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 65-69 
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    ISSN: 1432-1041
    Keywords: Paracetamol ; Malaria ; pharmacokinetics ; phase II conjugation ; glucuronidation ; sulphation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Investigations in animals have suggested that conjugation of paracetamol may be reduced in malaria. We have measured plasma concentrations and the urinary excretion of paracetamol and its phase II metabolites in eight Thai patients during uncomplicated falciparum malaria and in convalescence, following a 1000 mg single oral dose. The apparent oral clearance (Malaria, 3.6; Convalescence, 3.9; ml·min−1·kg−1), the elimination half-life (Malaria, 3.8; Convalescence, 3.7 h) and apparent volume of distribution (Malaria, 1.2; Convalescence, 1.2; l·kg−1) of paracetamol were similar during malaria and convalescence. In addition, the urinary excretion of paracetamol and its major phase II metabolites and their formation clearances from paracetamol were not significantly different between the two study phases. These data show that clinical malaria infection has no effect on the conjugation of paracetamol in man.
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    URL: http://dx.doi.org/10.1007/BF00202175
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  • 23
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    The acetylation phenotype: does it contribute to the non-linearity of the metabolite pharmacokinetics of metamizol? (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 79-80 
    Details
    ISSN: 1432-1041
    Keywords: Metamizol ; Acetylation phenotype ; metabolites ; pharmacokinetics ; dose-linearity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00202178
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  • 24
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    Relative bioavailability of nicotine from a nasal spray in infectious rhinitis and after use of a topical decongestant (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 71-75 
    Details
    ISSN: 1432-1041
    Keywords: Nicotine ; Rhinitis ; pharmacokinetics ; nasal spray ; xylometazoline ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The relative bioavailability of nicotine from a nasal spray was assessed in 15 smokers suffering a common cold and rhinitis according to generally accepted criteria. The patients were given a single dose of 2 mg nicotine from the nasal spray with and without concurrent administration of a nasal vasoconstrictor decongestant, xylometazoline, in randomised order. Control session measurements were made in the disease-free state. Applying strict bioequivalence criteria, we found that common cold/rhinitis slightly reduced the bioavailability of nicotine, both in its rate and extent; the geometric mean of the ratio of Cmax, AUC and tmax were 0.81, 0.93 and 1.36, respectively. The nasal vasoconstrictor, xylometazoline, normalised the extent of the bioavailability of nicotine, but further prolonged the time for absorption to almost twice that measured in the disease-free state, increasing the tmax ratio to 1.72. The results suggest that a minor proportion of people stopping smoking with the help of a nicotine nasal spray may experience a minor reduction in the effect of the spray during common cold/rhinitis. However, the nicotine self-titration behaviour found with most smoking cessation products (except the nicotine patch) will automatically lead to an adjustment of the dosage to achieve the desired effect.
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  • 25
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    Effects of liver disease on the pharmacokinetics of intravenous and oral chlordesmethyldiazepam (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 265-268 
    Details
    ISSN: 1432-1041
    Keywords: Chlordesmethyldiazepam ; Liver disease ; pharmacokinetics ; i.v./p.o. administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract We studied the pharmacokinetics of a single 0.5-mg i.v. dose of chlordesmethyldiazepam in 8 patients with liver disease and in 12 age-matched healthy controls. The kinetics were also studied of a single 1-mg oral dose in the patients with liver disease. After i.v. administration the kinetics of total chlordesmethyldiazepam in patients with liver disease differed from those in controls: elimination half-life was almost twice that in controls (395 and 204 h), as a consequence of a marked reduction in total clearance (0.13 and 0.25 ng·ml−1·h−1), whereas the apparent volume of distribution was similar in patients and controls (4.7 and 3.9 1/kg−1). The free fraction of the drug in patients was higher (5.5%) than in controls (2.9%). Correction for differences in protein binding revealed clearance in the patients was one-fifth (1.8 and 10.5 ng ml−1·kg−1) and volume of distribution one-half (65.0 and 118.4 1·kg−1) that in controls. The systemic availability of oral chlordesmethyldiazepam was high (110%) in spite of a relatively slow absorption rate. These results indicate a need for caution in the administration of chlordesmethyldiazepam to patients with liver disease.
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    URL: http://dx.doi.org/10.1007/BF00198309
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  • 26
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    Effects of a finnish sauna on the pharmacokinetics and haemodynamic actions of propranolol and captopril in healthy volunteers (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 133-137 
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    ISSN: 1432-1041
    Keywords: Sauna ; Propranolol ; Captopril ; pharmacokinetics ; blood pressure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The effects of a Finnish sauna on propranolol pharmacokinetics and on the pharmacodynamics of propranolol and captopril were studied in healthy, young volunteers (2 males, 6 females) in a double-blind, cross-over trial. The subjects received single oral doses of placebo. propranolol (40 mg) or captopril (12.5 mg) in sauna and control sessions at a one-week interval. The sauna sessions consisted of three repetitive 10-min stays in a sauna (85–100°C, relative humidity 25–35%) separated by two 5-min rest periods in a cool room. Sauna bathing started 35, 50 and 65 min after ingestion of the drugs. Venous blood for plasma propranolol measurement were collected before and 15, 30, 45, 60, 75, 90 min and 2, 3, 4, 5, 7 and 24 h after drug intake. The sauna significantly increased the maximum concentration (Cmax 41 vs. 28 ng·ml−1) of propranolol and the mean plasma propranolol concentration 60 and 90 min, and 2 and 3 h after drug administration. It also significantly increased the AUC0–5h (119 vs 71 μg·h·l-1) of propranolol from 0 to 5 hours tmax, t1/2β and AUC0–24h of propranolol did not differ between the control and sauna sessions. The higher propranolol levels during and after the cessation of sauna bathing did not lead to significant changes in blood pressure or heart rate compared to the control period. Captopril had no major effects on these parameters during the post-sauna phase. The results suggest that a sauna may increase the plasma propranolol concentration, but that did not notably affect the blood pressure or heart rate in healthy, young volunteers during the post-sauna phase.
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    URL: http://dx.doi.org/10.1007/BF00192738
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  • 27
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    Pharmacokinetic interactions of alcohol and acetylsalicylic acid (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 151-153 
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    ISSN: 1432-1041
    Keywords: Ethanol ; Acetylsalicylic acid ; ibuprofen ; paracetamol ; non-steroidal anti-inflammatory drugs ; interactions ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract This study assessed the influence of acetylsalicylic acid (ASA, 1.0 g), ibuprofen (0.8 g) and paracetamol (1.0 g) on the single-dose kinetics of ethanol in 12 healthy volunteers ingesting the drug and a standardised 1840-kJ breakfast 1 h before intake of ethanol. It also assessed the influence of ethanol on the single-dose kinetics of 1.0 g ASA in ten fasting healthy volunteers. Plasma concentrations of ethanol were measured by gas chromatography, and those of the drugs by liquid chromatography. There was no effect of ASA, ibuprofen or paracetamol on the single-dose kinetics of ethanol, but concurrent intake of ethanol reduced the peak concentration of ASA by 25%.
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  • 28
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    Influence of piroxicam coadministration on pharmacodynamic parameters and the plasma concentration/effect relationship of recombinant hirudin (CGP 39393) (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 241-246 
    Details
    ISSN: 1432-1041
    Keywords: Recombinat hirudin ; Piroxicam ; activated partial thromboplastin time ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Recombinant hirudins are currently under investigation for use in myocardial infarction and unstable angina. In this study the influence of piroxicam on the pharmacodynamics and pharmacokinetics of a recombinant hirudin preparation (CGP 39393) administered intravenously was determined. Twelve healthy, male volunteers received piroxicam 10 mg and matching placebo once daily for 12 days according to a double-blind, randomised cross-over design. On the 12th day, the dose of piroxicam was followed by a 6-hour infusion of hirudin 0.1 mg·kg−1·h−1. Plasma concentrations and urinary excretion of hirudin and repeated measurements of the activated partial thromboplastin time (APTT), bleeding time and platelet adhesion index were assessed up to 24 h after the start of the infusion. The maximum APTT was 83 s (placebo) and 84 s (piroxicam), 3 to 4 h after the start of the infusion, and was comparable on both study days. The AUD0–24 (APTT) came to 913 s·h·kg−1 under placebo and it was slightly increased to 1,017 s·h·kg−1 after piroxicam; the 95%-confidence interval according to MOSES ranged from 0.97 to 1.24, and the point estimator was 1.10. Bleeding time was significantly prolonged from 290 s under placebo to 345 s under piroxicam before the start of the infusion of hirudin. No further prolongation was found during or after the infusion. No change was observed in the platelet adhesion index. Responsiveness parameters according to a sigmoidal Emax-model were obtained from the hirudin-plasma concentration/effect (i.e. APTT-prolongation)-curves after placebo and piroxicam. Maximal APTT-prolongation (Emax; i.e. peak APTT minus the baseline value) was 53 s after placebo and 52 s after piroxicam. The EC50 was 34 nmol·l−1 after placebo and 40 nmol·h·l−1 after piroxicam. The AUC0 of hirudin was to 539 nmol·h·l−1·kg−1 under placebo and 557 nmol·h·l−1·kg−1 after piroxicam coadministration; the 95%- confidence interval according to MOSES ranged from 0.95 to 1.14, and the point estimator was 1.03. No period effect was detected. There were no significant differences between the other pharmacokinetic parameters except Vss, which was increased slightly from 0.23 l to 0.27 l under piroxicam. The results do not show a clinically relevant pharmacodynamic and/or pharmacokinetic interaction between hirudin and piroxicam.
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    Pharmacokinetics of fluconazole after oral administration in children with human immunodeficiency virus infection (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 291-293 
    Details
    ISSN: 1432-1041
    Keywords: Fluconazole ; absorption ; pharmacokinetics ; HIV infection ; children
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The objective of this study was to determine the pharmacokinetics of fluconazole after oral administration in children with human immunodeficiency virus (HIV) infection. After an overnight fast, a single dose of either 2 mg·kg−1 or 8 mg·kg−1 was administered in a suspension; five children received 2 mg·kg−1 and four 8 mg·kg−1 (ages 5–13 years). Blood samples were collected at various times on day 1, and once daily on days 2–7 after the dose. Fluconazole serum concentrations were measured by gas chromatography. At the dose of 2 mg·kg−1, the Cmax, AUC (0–∞), and t1/2 ranged from 2.3–4.4 μg·ml−1, 84.9–136 μg·h·ml−1, and 19.8–34.8 h, respectively. At the dose of 8 mg·kg−1 the Cmax, AUC (0–∞), and t1/2 ranged from 5.4–12.1 μg·ml−1, 330–684 μgh·ml−1, and 25.6–42.3 h, respectively. When compared with published data in healthy adults, fluconazole achieved similar serum concentrations in the present group of children, indicating a nearly complete degree of absorption.
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    URL: http://dx.doi.org/10.1007/BF00198314
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    Humoral and haemodynamic effects of idrapril calcium, the prototype of a new class of ACE-inhibitors, in essential hypertensive patients (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 339-343 
    Details
    ISSN: 1432-1041
    Keywords: Idrapril ; ACE-inhibition ; Hypertension ; essential ; active renin ; angiotensin II ; blood pressure ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Idrapril is the prototype of a new class of ACE inhibitors, characterised by the presence of a hydroxdmic group. Six untreated in-patients with essential hypertension were given single oral doses of the calcium salt of idrapril, idrapril calcium (200 mg) and placebo according to a double blind, randomised experimental design. Supine and upright blood pressure, heart rate, plasma idrapril serum ACE, active renin and angiotensin II were measured at timed intervals for 24 hours after dosing. Plasma idrapril reached a peak after 2 hours (3.01 μ·ml−1), and by 12 hours the compound had al most disappeared (67 ng·ml−1). Derived t1/2 was 1.4–2.2 h. ACE activity was suppressed [from 77.9 to 3.3 after 2 hours and 11.8 after 12 hours nmol−1·min−1·ml] and angiotensin II production inhibited [from 8.8 to 3.1 (after 1 hour) and 7.5 (after 12 hours) pg·ml−1] for up to 12 h, while active renin rose up to 24 h [from 12.3 to 20.1 (after 8 hours) and 17.5 (after 24 hours) pg·ml−1]. Compared to placebo, idrapril calcium significantly lowered both supine blood pressure starting at 4 hours (idrapril calcium 140/93 mmHg; placebo 157/101 mmHg) up to 24 hours (idrapril calcium 142/91 mmHg; placebo: 155/97 mmHg), and upright blood pressure starting at 3 hours (idrapril calcium 135/95 mmHg; placebo 147/100 mmHg) up to 24 hours (idrapril calcium 132/92 mmHg; placebo 145/100 mmHg). Idrapril calcium appears to be an effective ACE inhibitor in essential hypertension, with a hypotensive action for up to 24 h.
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    Relative bioavailability of cyclosporin from conventional and microemulsion formulations in heart-lung transplant candidates with cystic fibrosis (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 285-289 
    Details
    ISSN: 1432-1041
    Keywords: Cyclosporin ; Cystic fibrosis ; pharmacokinetics ; bioavailability ; formulation ; transplantation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Patients with cystic fibrosis absorb cyclosporin poorly and erratically. We have compared the relative bioavailability of cyclosporin from conventional and microemulsion formulations in 5 adult heart-lung transplant candidates with cystic fibrosis. Relative bioavailability was compared at two dose levels (200 mg and 800 mg). A randomized 4-period cross-over study was performed with at least a 7 days washout period between each single dose pharmacokinetic study. Blood cyclosporin concentrations were measured by a selective monoclonal antibody-based radioimmunoassay. The bioavailability of cyclosporin from the microemulsion formulation was 1.84 (95% C.I. 1.05 to 3.22; P−0.04) and 2.09 (95% C.I. 0.95 to 4.61; P−0.06) times higher compared with the conventional formulation at 200 mg and 800 mg respectively. Cmax following the microemulsion formulation was 3.38 (C.I. 1.14 to 10.59; P−0.04) and 2.77 (C.I. 1.48 to 5.19; P−0.01) times higher compared with the conventional formulation at 200 mg and 800 mg respectively. The higher Cmax following the microemulsion formulation was accompanied by shorter tmax. An enhancement of cyclosporin absorption with the microemulsion formulation was demonstrated in each patient for at least one dose level. We conclude that rate and extent of cyclosporin absorption from the microemulsion formulation is greater compared with the conventional formulation in patients with cystic fibrosis. The potential therapeutic and economic benefits of the micro-emulsion formulation should be evaluated in cystic fibrosis patients following heart-lung transplantation.
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    URL: http://dx.doi.org/10.1007/BF00198313
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    Pharmacokinetic-pharmacodynamic (PK-PD) modeling for a new antihypertensive agent (neutral metalloendopeptidase inhibitor SCH 42354) in patients with mild to moderate hypertension (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 351-359 
    Details
    ISSN: 1432-1041
    Keywords: Atrial natriuretic peptide ; Hypertension ; SCH 42354 ; blood pressure ; neutral metalloendopeptidase ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract SCH 42354, a neutral metalloendopeptidase (NEP) inhibitor, is the pharmacologically active form of the prodrug SCH 42495. It exerts antihypertensive effects by potentiating atrial natriuretic peptide (ANP) activity through inhibition of its hydrolysis by NEP. The objective of this study was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of SCH 42354 in hypertensive males. SCH 42495 12.5 to 400 mg was administered orally to hypertensive men twice daily in a double-blind, placebo controlled multiple-dose parallel group design. Plasma SCH 42354 concentration and diastolic blood pressure (DBP) data were used to develop a PK-PD model using two approaches. In the first (non-integrated) approach, the “link” model was used to predict effect-site concentrations, and was applied to data obtained at the 300 and 400 mg BID doses only; data at the other (lower) doses were not amenable to modeling because of high variability. Effect-site concentration and DBP data were then fit to a sigmoid Emax PD model. For the 300 mg BID dose, PD parameters were: maximum effect (Emax), 8.1mmHg; no-drug effect (Eo), 3.6 mmHg; concentration corresponding to 50% of maximum response (EC50), 0.87 μg·ml−1; and gamma, 3.9. In the second (time-integrated) approach, plasma SCH 42354 concentration and effect data obtained over the entire dose range were integrated with respect to time. Average plasma concentration and DBP data were then fit to a simple Emax PD model. PD parameters obtained over the dose range were: Emax, 10.3 mmHg; Eo, 2.0 mmHg; and EC50, 0.7 μg·ml−1. These were similar to the estimates obtained from the first approach, demonstrating that the integrated (average) data allow PK-PD modeling over the (entire) dose range. The analysis showed that, at steady-state, a 400 mg BID dose of SCH 42495 produced an approximate 10 mmHg decrease in DBP in hypertensive males; the average plasma SCH 42354 concentration attained at this dose was approximately 1.8 μg·ml−1.
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    Electronic Resource
    The effect of pH on the buccal and sublingual absorption of captopril (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 373-379 
    Details
    ISSN: 1432-1041
    Keywords: Captopril ; sublingual ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The effect of pH on the buccal and sublingual absorption of captopril was evaluated using in vitro techniques and human studies. Partitioning of captopril into n-octanol was lowest over the pH range 5 to 8 and highest at pH values 3, 4 and 9. Using the buccal absorption technique, the partitioning of captopril (2 mg) was examined in six healthy male volunteers from buffered solutions (pH 3, 4, 5, 6, 7, 8, and 9). Lowest buccal partitioning occurred at pH 3 while maximal buccal partitioning occurred at pH 7. These data clearly indicated that the buccal absorption of captopril did not obey the classical pH/partition hypothesis suggesting that mechanisms other than passive diffusion were involved in its absorption. Captopril pharmacokinetic and pharmacodynamic parameters were determined after administration of buffered sublingual captopril (pH 7, optimal pH for absorption as determined from the buccal partitioning data) and unbuffered sublingual captopril. The study was performed in eight healthy volunteers in a randomised single-blind cross-over fashion. The tmax for captopril was found to be approximately 11 minutes earlier after buffered versus unbuffered sublingual administration and AUC0–30 min increased by approximately 30% in the case of buffered captopril. Cpmax, AUC0–180 min and relative bioavailability did not differ between the buffered and unbuffered administration. Pharmacodynamic parameters (BP, heart rate and plasma renin activity) did not differ significantly between buffered and unbuffered sublingual administration. The increased rate of captopril absorption after buffered sublingual administration was small and is likely to offer little therapeutic advantage over conventional sublingual formulation.
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    URL: http://dx.doi.org/10.1007/BF00194953
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    Plasma and red blood cell pharmacokinetics of pimobendan enantiomers in healthy Chinese (1995)
    Springer
    European journal of clinical pharmacology 47 (1995), S. 537-542 
    Details
    ISSN: 1432-1041
    Keywords: Pimobendan ; enantiomers ; pharmacokinetics ; stereoselectivity ; demethyl pimobendan ; metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics of enantiomers of pimobendan and their demethylated metabolites in plasma and red cells were studied in 8 normal healthy volunteers. After racemic pimobendan 5 mg IV, the plasma concentration-time curve followed a two-compartment open-model with elimination half-lives of 1.81 h and 1.86 h for (+)- and (−)-pimobendan, respectively. The clearances and volumes of distribution postequilibrium were 13.5 ml · min−1 · kg−1, 14.4 ml · min−1 · kg−1; 1.74 l · kg−1 and 2.34 l · kg−1 for (+)- and (−)-pimobendan, respectively. Plasma protein binding (n=3) of (+)-, (−)-pimobendan, (+)- and (−)-demethylated metabolites was 97.6, 97.6, 92.2 and 92.5%, respectively. The plasma concentration-time curve also followed a two-compartment open model after oral administration of 7.5 mg racemic pimobendan. The absolute bioavailabilities of (+)- and (−)-pimobendan were 0.51 and 0.55. Peak levels of (+)-and (−)-pimobendan, both at 1.2 h, were 15.8 and 16.8 ng · ml−1, respectively. The (+)- and (−)-pimobendan concentrations in red cells were determined and their pharmacokinetics were estimated using red blood cell data. Interesting phenomena were observed: the peak concentrations of (+)- and (−)-pimobendan in red blood cells were about 5.5- and 9.2-times higher than in plasma, and the AUCs were correspondingly elevated. The volume of distribution of the central compartment of (−)-pimobendan in red cell was significantly smaller than that of (+)-pimobendan. (0.24 vs. 0.42 l · kg−1.) Similar phenomena were found after IV administration. These all indicated stereoselective partitioning or distribution of (−)-pimobendan into red cells. Since the elimination half-life of (+)- and (−)-pimobendan in red cells was similar (3.07 vs 2.97 h), the highly significant difference in clearance between (+)- and (−)-pimobendan (3.7 vs 2.3 ml · min−1 · kg−1) was solely due to the stereoselective distribution of (−)-pimobendan into the red blood cells. This stereoselective property of the (−)-isomer may be the explanation of a previous report that (−)-pimobendan produced a 1.5-times larger contractile force in detergent-skinned preparations of cardiac muscle from guinea pig and dog than the (+)-isomer.
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    Pharmacokinetic and phase I studies of brequinar (DUP 785; NSC 368390) in combination with cisplatin in patients with advanced malignancies (1998)
    Springer
    Investigational new drugs 16 (1998), S. 19-27 
    Details
    ISSN: 1573-0646
    Keywords: phase I ; brequinar ; DUP 785 ; cisplatin ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Brequinar (DUP 785; NSC 368390) is a quinoline carboxylic acid derivative that inhibits pyrimidine synthesis at the level of dihydro-orotate dehydrogenase and revealed synergy with cisplatin in preclinical models. In this study investigating the pharmacokinetic and toxicity of brequinar in combination with cisplatin, patients were initially treated with weekly brequinar, in combination with an every-three-week administration of cisplatin. Due to toxicity, the schedule was modified to a 28-day cycle with brequinar given on days 1, 8, 15, and cisplatin on day 1. A total of 24 patients (16 male, 8 female; median age 57; median performance status 1) received 69 courses of therapy. Six dose levels were explored, with cisplatin/ brequinar doses, respectively, of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2. The serum concentration versus time curves for brequinar were biphasic. A comparison of the pharmacokinetic results after the first and third doses of brequinar indicate that the presence of 50, 60, and 75 mg/m2cisplatin did not change the protein binding and the pharmacokinetics of brequinar in any of the three brequinar-dose groups. Total cisplatin plasma pharmacokinetic followed a triphasic-shape curve and unbound cisplatin decayed at a very rapid rate. Since pharmacokinetic parameters for total cisplatin in this study were similar to those reported in the literature, the presence of brequinar is unlikely to alter the pharmacokinetics of cisplatin. Main dose-limiting toxicities included myelosuppression (including neutropenia and thrombocytopenia) and mucositis. Cisplatin/brequinar doses of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2, were associated with dose limiting toxicity in 0/3, 1/3, 1/3, 1/3, 2/4, 2/5, and 4/6 patients, respectively. This study shows that co-administration of brequinar and cisplatin does not affect the pharmacokinetic properties of either drug and that the MTDs of cisplatin/brequinar combinations are 60/860 mg/m2 or 75/650 mg/m2. From this study, we conclude that full dose of 75 mg/m2 cisplatin (day 1) can be administered with 650 mg/m2 brequinar (days 1, 8 and 15) without significant modifications of individual drug pharmacokinetic parameters.
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    Phase I clinical and pharmacokinetic trial of the podophyllotoxin derivative NK611 administered as intravenous short infusion (1998)
    Springer
    Investigational new drugs 16 (1998), S. 319-324 
    Details
    ISSN: 1573-0646
    Keywords: NK611 ; dimethylaminoetoposide ; Phase I ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Background: NK611 is a novel podophyllotoxin derivative. Compared with etoposide, NK611 carries a dimethyl-amino group at the D-glucose moiety. The antitumor activity of NK611 showed to be equal or superior to etoposide in a variety of in vitro and in vivo tumor models. The aim of our present study was to determine the maximum tolerated dose and the dose-limiting toxicities of NK611 administered as intravenous infusion over 30 min every 28 days. Patients and methods: 45 patients (7 female, 38 male; median age 54 [range 37–73]) were enrolled. In a first stage, NK611 was administered without hematopoietic growth factor support; in a second stage, G-CSF was used for further dose escalation. Toxicities were assessed using WHO-criteria. Results: Initially, the dose was escalated from 60 mg/m2 to 120 mg/m2. In a second patient cohort, doses were further escalated with G-CSF support with doses ranging from 140 mg/m2 to 250 mg/m2. Dose-limiting toxicities were granulocytopenia and thrombocytopenia. Non-hematologic toxicities consisted of alopecia, mild nausea, and infection. Four partial responses were observed: two at 200 mg/m2 (pleural mesothelioma, response duration 7 months, and non-small cell lung cancer, response duration 13 months), and two at 250 mg/m2 (hepatocellular carcinoma, response duration 7 months, and non-small cell lung cancer, response duration 2 months). Pharmacokinetic analyses were performed in all patients. Using an open 3-compartment model, the terminal half-life (t1/2γ) was 14.7 ± 3.7 h. The AUC at 250 mg/m2 was determined to be 330 ± 147 μg/mlh, the plasma clearance of NK611 was 16.2 ± 8.2 ml/min · m2 and the Vss was 16.8 ± 3.3 l/m2. Protein binding of NK611 was 98.7%. Conclusion: the recommended dose for clinical Phase II studies is 120 mg/m2 without G-CSF support and 200 mg/m2 with G-CSF support.
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    A phase II and pharmacokinetic study of 6S-leucovorin plus 5-fluorouracil in patients with colorectal carcinoma (1995)
    Springer
    Investigational new drugs 13 (1995), S. 149-155 
    Details
    ISSN: 1573-0646
    Keywords: leucovorin ; colorectal cancer ; pharmacokinetics ; chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Leucovorin (LV) is commonly used as a modulator of 5-fluorouracil (5-FU) cytotoxicity. In patients with colon cancer, the addition of LV to 5-FU improves response rates, and in some trials has improved survival in advanced disease and in the adjuvant setting. Leucovorin is generally administered as a racemic mixture, but the isomers differ substantially in pharmacokinetics and biological activity, with 6S-LV the predominant active component. The current study was undertaken to determine the effect of 6R on the pharmacokinetics of 6S-LV, and to characterize the toxicity and antitumor effect of 5-FU when administered with 6S-LV to patients with advanced colorectal carcinoma. Thirty patients were treated with weekly 5-FU plus high dose 6S-LV. To determine the effects of 6R-LV on the pharmacokinetics of 6S-LV, 20 patients were randomly assigned to receive either 250 mg/m2 6S-LV or 500 mg/m2 6R,S-LV as a 2 hour IV infusion on day −2, and the other preparation on day −1, with pharmacokinetics measured each day. The presence of 6R-LV had no effect on the AUC, Clp, Cmax, or terminal phase t1/2 of 6S-LV. The overall response rate was 40% (C.I. 23–60%). The most frequent toxicities were gastrointestinal. In this small cohort, scheduled and delivered dose intensity was positively associated with response (p=0.05). These results show that there is no pharmacokinetic advantage to the use of 6S-LV rather than 6R,S-LV as a modulator of 5-FU.
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    URL: http://dx.doi.org/10.1007/BF00872864
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    Pharmacokinetics and Relative Bioavailability of Carboxyamido-Triazole with Respect to Food and Time of Administration: Use of a Single Model for Simultaneous Determination of Changing Parameters (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 673-687 
    Details
    ISSN: 1573-8744
    Keywords: carboxyamido-triazole ; bioavailability ; chronopharmacology ; pharmacokinetics ; food
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Carboxyamido-triazole (CAI) is an anti-invasive, antimetastatic, antiangiogenic agent in clinical development for cancer treatment. It has been postulated that food might enhance the oral absorption of micronized CAI based on an apparent discrepancy in steady state maximum concentrations when taken without regard to meals vs. fasting. The purpose of this study was to determine if a standardized meal affects the absorption and pharmacokinetics of this agent. Twelve patients with refractory cancers and good end organ function were randomized to receive two doses of CAI (250 mg/m 2 ) with and without a standardized high fat meal. One cohort of 6 patients received these doses at 9 AM, and the remaining 6 patients received CAI at 9 PM. Blood was obtained prior to each dose, and serially thereafter. A series of pharmacokinetic (PK) models were fit to the concentration–time data. PK parameters were ultimately calculated using a model which allows simultaneous estimation of parameters from both test doses using nonlinear least squares analysis with ADAPT II. This model estimates independent absorption rate constants and relative fraction absorbed for each condition. AUC 0–t was determined using the trapezoidal method, extrapolated to infinity, and used to calculate the relative bioavailability. No significant differences in PK parameters were noted between the morning and evening cohorts. However, the relative bioavailability, as measured by AUC 0–∞, of CAI was significantly increased when administered with a high fat meal compared to fasting (138.9 vs. 52.2 μg * hr/ml; p=0.0005). The magnitude of the increase in relative bioavailability of CAI taken with food could have profound implications for patients who may inadvertently take this medication shortly after eating.
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    URL: http://dx.doi.org/10.1023/A:1020750923542
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    Pharmacokinetics of Antimony in Patients Treated with Sodium Stibogluconate for Cutaneous Leishmaniasis (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 113-116 
    Details
    ISSN: 1573-904X
    Keywords: antimony ; sodium stibogluconate ; pentavalent antimonials ; pharmacokinetics ; cutaneous leishmaniasis ; antimony in whole blood ; urinary excretion of antimony ; interpatient variability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of Sb was examined in 29 patients with cutaneous leishmaniasis following the intramuscular administration of a dose of sodium stibogluconate equivalent to 600 mg of Sb. Blood was sampled at different time intervals from each patient and Sb was measured in whole blood by electrothermal atomic absorption spectrophotometry after an appropriate dilution with Triton X-100. The 24-hr urine- was also collected and analyzed similarly. The blood concentration-time data conformed to the one-compartment open model with mean and (SEM) of the apparent first-order rate constants for absorption (ka) and elimination (kd) of 1.71 (0.15) and 0.391 (0.016) hr−1, respectively. The maximum concentration of Sb achieved was 8.77 (0.39) mg/L and the peak time was 1.34 (0.09) hr. The total body clearance (TBC) and the volume of distribution (Vd) were 17.67 (1.38) L/hr and 45.7 (2.6) L, respectively, assuming a complete absorption. The fraction of dose of Sb excreted in the urine was 0.80 (0.07) and the renal clearance was 12.7 (1.16) L/hr. The frequency distribution pattern of the area-under-the-curve (AUC) appears to be bimodal and separates patients into those with low exposure to Sb (AUC = 11.7-29.04 mg.hr/L) (i.e., rapid eliminators) and those with high exposure to Sb (AUC = 31.5-49.1 mg.hr/ L) (i.e., slow eliminators). This may explain the variability observed in the response to treatment of leishmaniasis with sodium stibogluconate.
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    URL: http://dx.doi.org/10.1023/A:1016251023427
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    Assessment of Toxicokinetics and Toxicodynamics Following Intravenous Administration of Etoposide Phosphate in Beagle Dogs (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 117-123 
    Details
    ISSN: 1573-904X
    Keywords: BMY-40481 ; etoposide phosphate ; etoposide ; pharmacokinetics ; pharmacodynamics ; dogs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The toxicokinetics and toxicodynamics of etoposide phosphate (BMY-40481), a water soluble phosphate ester derivative of etoposide, were investigated in beagle dogs (N = 4) following 5 min i.v. infusion doses equivalent to 57, 114 and 461 mg/m2 of etoposide. The doses were administered in sequence starting with the low dose. There was a 28 day wash-out period between the doses. Serial blood samples were collected over 32 hr and the levels of intact BMY-40481 and etoposide in plasma were measured using validated HPLC assays. Hematology profiles were obtained at pre-dose, and twice a week post-dose for 28 days to correlate systemic exposure to etoposide and hematologic toxicity. Following i.v. administration, plasma concentrations of BMY-40481 declined rapidly. For the 3 doses, mean t1/2 of BMY-40481 ranged from 0.11 - 0.17 hr (6.6-11 min). The mean Cmax and AUC values of BMY-40481 ranged from 1.72 - 40.5 µg/ml and 0.16 - 4.14 hr.µg/ml, respectively. Both systemic clearance and steady state volume of distribution of BMY-40481 decreased significantly at the high dose. In contrast, the mean Cmax and AUC values of etoposide ranged from 5.46 - 39.4 µg/ml and 2.28 - 22.6 hr.µg/ml, respectively. Cmax occurred at the end of infusion (5 min) at all dose levels, indicating that etoposide was rapidly formed from BMY-40481. The apparent systemic clearance (range: 342 - 435 ml/min/m2) and apparent steady state volume of distribution (range: 21.5 - 26.6 1/m2) of etoposide were dose-independent. The AUC of etoposide was significantly correlated with hematologic toxicity, i.e., percent decreases in white blood count (WBC), absolute neutrophil count (ANC) and platelets. The relationship was best described by the sigmoid Emax model for WBC and ANC, and by a simple linear model for platelets. Hemoglobin showed slight decreases which did not correlate with etoposide AUC. In summary, BMY-40481 is rapidly and extensively converted to etoposide; etoposide exhibits linear kinetics; and except for hemoglobin, hematologic toxicity is significantly correlated with etoposide exposure.
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    The Effect of Food on Pharmacokinetics of Zalcitabine in HIV-Positive Patients (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1462-1465 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; food ; interaction ; zalcitabine ; HIV infection
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of this study was to determine the effect of food on the pharmacokinetics of zalcitabine in HIV-positive patients. Methods. Twenty patients received single oral 1.5 mg doses of zalcitabine with and without a standard breakfast in an open-label, randomized crossover study with at least a one week washout period between treatments. Serial blood and urine samples were collected over 24 hours and assayed for zalcitabine by a modified GC/MS method. Results. Administration with food delayed and prolonged absorption resulting in a decrease of approximately 39% in maximal plasma concentrations compared to dosing under fasting conditions. Comparison of plasma AUC values indicated a small (14%) reduction in bioavailability when given with food. Approximately 59% and 45% of the dose were excreted unchanged in the urine under fasting and fed conditions, respectively. Conclusions. The results of this study show that the administration of zalcitabine with food results in a mild reduction in bioavailability. Although these changes are not expected to be of clinical importance, further studies must be conducted for confirmation.
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  • 42
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    A Novel Oligodeoxynucleotide Inhibitor of Thrombin. II. Pharmacokinetics in the Cynomolgus Monkey (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1943-1947 
    Details
    ISSN: 1573-904X
    Keywords: GS-522 ; oligodeoxynucleotide ; thrombin ; pharmacokinetics ; monkey
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To determine the pharmacokinetics of GS-522, an oligodeoxynucleotide (GGTTGGTGTGGTTGG) inhibitor of thrombin, after constant infusion and bolus administration in the cynomolgus monkey. Methods. Using a stability indicating HPLC method, the GS-522 plasma concentration versus time data were obtained after constant infusion (0.1, 0.3, 0.5 mg/kg/min) and bolus administration (11.25 and 22.5 mg/kg). Plasma data after bolus administration was fit to a three-compartment model. Results. The half-lives for the α and β phases were 1.4 and 5.4 min, respectively. Steady state GS-522 concentrations were reached within 10 minutes after initiation of constant infusions. Termination of infusions resulted in a rapid elimination of GS-522 with an average elimination half-life equal to 1.5 min. The Vss calculated from both the constant infusion and bolus data approximated the blood volume of the monkey. Substitution of the phosphodiester backbone at the 3′ end of GS-522 with two phosphorothioate linkages did not substantially effect the elimination half-life upon termination of infusion. Conclusions. These data in conjunction with published biodistribution data suggest that oligodeoxynucleotides are rapidly cleared from plasma by tissue uptake and that little efflux back into blood takes place. Additionally, strategies designed to increase oligodeoxynucleotide resistance to exonucleases will not dramatically increase plasma half-lives.
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    URL: http://dx.doi.org/10.1023/A:1016295907266
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    Regional Drug Delivery II: Relationship Between Drug Targeting Index and Pharmacokinetic Parameters for Three Non-Steroidal Anti-Inflammatory Drugs Using the Rat Air Pouch Model of Inflammation (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1987-1996 
    Details
    ISSN: 1573-904X
    Keywords: drug targeting index ; regional administration ; pharmacokinetics ; rat air pouch model ; inflammation ; non-steroidal anti-inflammatory drugs ; diclofenac ; piroxicam ; S[ + ]ibuprofen ; albumin flux
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To quantify the advantage gained by direct administration to a target site for two non-steroidal anti-inflammatory drugs (NSAIDs) piroxicam and diclofenac in the rat air pouch model of inflammation. To derive a model relating drug targeting index (DTI) to the pharmacokinetic parameters of the target and systemic sites, and to compare predictions with observations. Methods. DTI was calculated based on area under the concentration time curve at target (pouch) and systemic site (venous blood) following administration into and sampling from both sites. A model was derived relating DTI to systemic clearance, target permeability, plasma protein binding and fraction of the targeted dose that is systemically available. Results. Both NSAIDs exhibited linear pharmacokinetics over the dose ranges studies. They differed primarily in total body clearance which was approximately 16 fold greater for diclofenac (213 ml hr−l per 250 g) than piroxicam (13 ml hr−l per 250 g). Observed DTIs (11, 114 and 276 for piroxicam, S[ + ]ibuprofen [studied previously] and diclofenac) were ranked in order of total body clearance but were approximately 7.5 fold lower than predicted (101, 700 and 2214 respectively). Conclusions. The discrepancy was explained by the influx of the plasma binding protein, albumin, into the target site due to increased vascular permeability associated with the inflammatory response. The originally derived equation for DTI, which assumed only unbound drug diffuses across the target site, was modified to take into account the simultaneous flux of bound drug.
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    URL: http://dx.doi.org/10.1023/A:1016212510900
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    Effects of Gender, Pregnancy, and Anesthesia on the Pharmacokinetics of Zidovudine in Rats (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1647-1651 
    Details
    ISSN: 1573-904X
    Keywords: zidovudine ; gender ; anesthesia ; pregnant ; pharmacokinetics ; rats
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The effects of gender, pregnancy and anesthesia on the pharmacokinetics of zidovudine (AZT) were studied in rats. Methods. Unanesthetized male (MR), female (FR) and pregnant (day 20, PR) rats received 50 mg/kg AZT via a jugular vein cannula. Female (FRA), pregnant (day 20, PRA) and pregnant (day 20, PRR) rats maintained under ketamine: acepromazine:xylazine anesthesia also received 50 mg/kg AZT. Two fetuses were removed at each sampling time from the PRR group. Plasma samples were collected and analyzed by RIA. Results. With the exception of a lower non-renal clearance in female rats, there were no gender differences in the disposition of AZT. No significant differences were noted in total clearance, non-renal clearance or volume of distribution between pregnant and female rats, however, significant differences in renal clearance values were evident. Anesthesia resulted in decreased total, renal and non-renal clearances in female and pregnant rats. The removal of fetuses during the experiments did not alter the total clearance of AZT in pregnant rats, however, renal clearance and volume of distribution were decreased by cesarian section. Conclusions. The rat appears to be a suitable laboratory animal model for investigating AZT disposition during pregnancy. However, results of pharmacokinetic studies when animals are maintained under anesthesia with ketamine :acepromazine:xylazine must be interpreted with caution.
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    URL: http://dx.doi.org/10.1023/A:1016293017318
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    Design for Cell-Specific Targeting of Proteins Utilizing Sugar-Recognition Mechanism: Effect of Molecular Weight of Proteins on Targeting Efficiency (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 209-214 
    Details
    ISSN: 1573-904X
    Keywords: protein targeting ; sugar recognition ; pharmacokinetics ; molecular weight ; liver
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Hepatic targeting of proteins utilizing the sugar-recognition mechanism was investigated in mice after intravenous injection. Five proteins with different molecular weights, i.e., bovine γ-globulins (IgG), bovine serum albumin (BSA), recombinant human superoxide dismutase (SOD), soybean trypsin inhibitor (STI), and chicken egg white lysozyme (LZM), were modified with 2-imino-2-methoxyethyl 1-thiogalactoside to obtain galactosylated proteins (Gal-IgG, Gal-BSA, Gal-SOD, Gal-STI, and Gal-LZM). The numbers of galactose residues were 38, 20, 11, 6, and 5 for Gal-IgG, Gal-BSA, Gal-SOD, Gal-STI, and Gal-LZM, respectively. All galactosylated proteins were dose-dependently taken up by the liver and the relative amount accumulated in the liver was decreased with an increase of the administered dose. At low doses (0.05 and 0.1 mg/kg), Gal-IgG, Gal-BSA, and Gal-SOD could be taken up by the liver up to more than 70–80% of dose within 10 min after intravenous injection, but the maximum amounts accumulated in the liver were approximately 40 and 30% of the dose for Gal-STI and Gal-LZM, respectively. Pharmacokinetic analysis revealed that the hepatic uptake clearance (CLliver) was quite different around the molecular weight of 32 kDa and correlated with the amount delivered to the liver; Gal-IgG, Gal-BSA, and Gal-SOD has a large CLliver that is close to the hepatic plasma flow rate (85 ml/hr), whereas those of Gal-STI and Gal-LZM were approximately 10 ml/hr at low doses. As for the total amount accumulated in the liver, high glomerular filtration rate of Gal-STI and Gal-LZM was also shown to cause insufficient delivery to the liver apart from being caused by their low CLliver.
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    Evaluation of Intestinal Absorption into the Portal System in Enterohepatic Circulation by Measuring the Difference in Portal–Venous Blood Concentrations of Diclofenac (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 880-883 
    Details
    ISSN: 1573-904X
    Keywords: portal–venous blood concentration difference ; enterohepatic circulation ; diclofenac ; portal system ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. We evaluated the first-pass effects in vivo by the intestine and liver during enterohepatic circulation (EHC) by simultaneously measuring the portal and venous plasma concentrations of the rat. Methods. The venous and upper portal blood vessels were cannulated through the jugular and the pyloric veins, respectively, to obtain simultaneously blood samples from both sites. After diclofenac was injected as a bolus through the jugular vein, the concentrations of diclofenac in the portal and jugular veins were measured at time intervals. The absorption rate from the intestinal tract into the portal system was determined using the portal–venous difference in plasma concentrations of diclofenac, considering 40% partitioning of diclofenac into erythrocytes. Results. After one hour, the plasma concentration in the portal vein was always higher than that in the jugular vein in awakening rats with intact EHC (portal–venous blood concentration difference). No portal–venous difference was observed in awakening rats with bile-duct cannulation. Therefore, it was concluded that this portal–venous concentration difference was not due to the hepatic clearance but to diclofenac reabsorption from the intestinal tract. Conclusions. Appropriately 40% of the dose of diclofenac was reabsorbed over 8 hours from the intestinal tract into the portal system. By comparing the reabsorbed amounts in the portal system and in the systemic circulation, the hepatic extraction ratio in vivo (FH) of diclofenac was estimated to be 63%.
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    Effect of Corticosteroid Binding Globulin on the Pharmacokinetics of Prednisolone in Rats (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 902-904 
    Details
    ISSN: 1573-904X
    Keywords: corticosteroid binding globulin ; transcortin ; pharmacokinetics ; free hormone hypothesis ; prednisolone ; methylprednisolone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The effect of exogenous corticosteroid binding globulin (CBG) on the pharmacokinetics of intravenous prednisolone was determined in rats to test the “free hormone hypothesis.” Methods. A dose of CBG to yield 95% binding with 1000 ng/ml of prednisolone in vitro in rat plasma or saline was administered before dosing 2 mg/kg of prednisolone hemisuccinate or methylprednisolone intravenously. Drug concentrations in plasma samples were assayed by HPLC. Results. Single administration of CBG decreased apparent prednisolone clearance by 56% (155 to 66 ml/min/kg) and reduced apparent Vss by 35% (4.1 to 2.7 L/kg) (p〈0.001). Methylprednisolone pharmacokinetics, studied as a negative control because the drug does not bind to CBG, did not change. Conclusions. The corticosteroid bound to CBG does not appear to be available for removal by clearance organs.
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    Metabolism of Dynorphin A 1-13 in Human Blood and Plasma (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1165-1170 
    Details
    ISSN: 1573-904X
    Keywords: dynorphin Al-13 ; opioid peptides ; metabolism ; pharmacokinetics ; HPLC
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. A detailed investigation of the metabolic routes and rates of Dyn A1-13 in human blood and plasma was performed. Methods. Human plasma was incubated at 37°C with dynorphin A 1-13 (Dyn Al-13, 15-20 µM). The generated dynorphin fragments were separated by a new ion-pair chromatographic method and identified by matrix assisted laser desorption mass spectroscopy. The kinetic behavior of parent compound and metabolites was evaluated in the absence and presence of enzyme inhibitors. Results. The major plasma metabolites of Dyn Al-13 were Dyn A1-12, A2-12, A4-12 and A4-8. Further metabolites were Dyn A2-13, A3-13, A3-12, A5-12, A6-12, A7-12, Al-10, A2-10, A2-8 and A3-8. At 37°C, Dyn Al-13 had a half-life of less than one minute in plasma and blood. Plasma half-lives of major metabolites ranged between 0.5 and 4 min. Inter-and intra-individual differences in healthy volunteers were 30% (c.v.). Dyn Al-13 is mainly metabolized by carboxypeptidases to Dyn Al-12 (80%) and by aminopeptidases to Dyn A2-13 (15%). Dyn A1-12 and Dyn A2-13 are predominantly converted into Dyn A2-12 (67% of Dyn Al-13). Subsequent metabolic steps yield Dyn A3-12 (16%), Dyn A4-12 (37%) and Dyn A4-8 (33%). Aminopeptidases generate Dyn A2-12, A3-12, A4-12, A5-12. ACE metabolizes Dyn Al-12 (19%), A2-12 (33%), A3-12 (34%) and A4-12 (46%). Bestatin-sensitive endopeptidases (possibly endopeptidase 24.11) metabolize 30% of Dyn A2-12. Dyn A4-8 is formed via Dyn A4-12 (23% of Dyn A4-12) and Dyn A2-10 (37% of Dyn A2-10). Conclusions. The combination of enzyme inhibition experiments and noncompartmental kinetic analysis proved to be a powerful tool for the detailed evaluation of the metabolic fate of Dyn Al-13 in human blood and plasma.
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    Pharmacokinetic Studies of Methotrexate in Plasma and Synovial Fluid Following IV Bolus and Topical Routes of Administration in Dogs (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1474-1477 
    Details
    ISSN: 1573-904X
    Keywords: methotrexate ; pharmacokinetics ; synovial fluid ; poloxamer gel ; muscle tissue
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The pharmacokinetic properties of methotrexate (MTX) in the plasma and synovial fluid (SF) after bolus IV and topical administration were studied in dogs to assess the feasibility of topical delivery of MTX for the treatment of rheumatoid arthritis. Methods. A MTX gel in Poloxamer 407 containing an absorption enhancer was formulated and topically applied on the elbow and stifle joints of dogs. SF was collected by inserting a needle with syringe into the joint space. Drug concentrations in the plasma, SF and muscle tissues were determined using a HPLC method with fluorimetric detection. Results. Peak MTX concentrations in SF occurrred at 38 ± 5 min following bolus IV dose, indicating the presence of a substantial diffusion barrier between the plasma and SF. The plasma/SF concentration ratios of 1.16 ± 0.25 were maintained after the attainment of distribution equilibrium between the two compartments. The t1/2 values in the plasma (11.2 ± 1.2 hr) and SF (12.7 ± 3.7 hr) were similar during the elimination phase, while the MRT in SF (3.24 ± 0.21 hr) was longer than that in plasma (2.56 ± 0.20 hr), probably due to the slow distribution of MTX to SF. After topical dose, MTX concentrations in plasma reached the steady state at ~4 hr, lasting for ~20 hr.The bioavailability of MTX from the gel was 11.8 ± 3.3% of the applied dose, but muscle tissues beneath the gel application site had significantly higher levels of MTX than untreated muscle tissues. There was no statistical difference in SF concentrations of MTX between drug treated and untreated joints 24 hr after topical dose. Conclusions. Topical delivery of MTX in a hydrophilic gel achieved a sustained C/t profile in plasma and higher drug levels in muscle tissues underneath the dosing site, implicating the potential therapeutic value of the topical formulation. Methods. A MTX gel in Poloxamer 407 containing an absorption enhancer was formulated and topically applied on the elbow and stifle joints of dogs. SF was collected by inserting a needle with syringe into the joint space. Drug concentrations in the plasma, SF and muscle tissues were determined using a HPLC method with fluorimetric detection. Results. Peak MTX concentrations in SF occurrred at 38 ± 5 min following bolus IV dose, indicating the presence of a substantial diffusion barrier between the plasma and SF. The plasma/SF concentration ratios of 1.16 ± 0.25 were maintained after the attainment of distribution equilibrium between the two compartments. The t1/2 values in the plasma (11.2 ± 1.2 hr) and SF (12.7 ± 3.7 hr) were similar during the elimination phase, while the MRT in SF (3.24 ± 0.21 hr) was longer than that in plasma (2.56 ± 0.20 hr), probably due to the slow distribution of MTX to SF. After topical dose, MTX concentrations in plasma reached the steady state at ~4 hr, lasting for ~20 hr.The bioavailability of MTX from the gel was 11.8 ± 3.3% of the applied dose, but muscle tissues beneath the gel application site had significantly higher levels of MTX than untreated muscle tissues. There was no statistical difference in SF concentrations of MTX between drug treated and untreated joints 24 hr after topical dose. Conclusions. Topical delivery of MTX in a hydrophilic gel achieved a sustained C/t profile in plasma and higher drug levels in muscle tissues underneath the dosing site, implicating the potential therapeutic value of the topical formulation.
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    Intra- and Inter-Subject Variabilities of CGP 33101 after Replicate Single Oral Doses of Two 200-mg Tablets and 400-mg Suspension (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1878-1882 
    Details
    ISSN: 1573-904X
    Keywords: CGP 33101, intra-subject variability ; inter-subject variability ; pharmacokinetics ; healthy subjects ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of this study was to use a replicate designed trial to assess the overall, intra- and inter-subject variabilities in pharmacokinetic parameters of CGP 33101 after oral administration of tablets relative to that of powder suspended in water, and to determine the relative proportion of the intra-subject variance to the overall variability. Methods. Sixteen healthy subjects were randomly assigned to four groups to receive tablets and suspension twice in four different treatment sequences. The plasma concentration-time profile of CGP 33101 was characterized in terms of Cmax, Tmax, and AUC. Bioavailability of tablets relative to suspension and intra- and inter-subject variability were assessed by statistical analysis. Results and Conclusions. The overall variabilities in absorption kinetics of CGP 33101 in healthy subjects were small with CV's of the population mean values for AUC and Cmax less than 26% for both tablets and suspension. Contribution of intra-subject variability to the overall variability was also small (~20%). Both the overall and intra-subject variabilities of AUC and Cmax after suspension were larger than after the tablets. However, the differences in variability between tablets and suspension were not statistically significant (p 〉 0.05). The tablet formulation was bioequivalent to suspension in terms of rate and extent of absorption based on 90% conventional confidence intervals (for AUC and Cmax) and Wilcoxon rank-sum test (for Tmax).
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    URL: http://dx.doi.org/10.1023/A:1016275402723
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    Effect of Probenecid on the Enantioselective Pharmacokinetics of Oxprenolol and Its Glucuronides in the Rabbit (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1964-1967 
    Details
    ISSN: 1573-904X
    Keywords: enantioselectivity ; pharmacokinetics ; oxprenolol ; oxprenolol glucuronides ; probenecid ; active renal secretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To study the effect of probenecid on the stereoselective pharmacokinetics of oxprenolol and its glucuronides in the rabbit. Methods. An oral dose of 50 mg/kg racemic oxprenolol was given to nine rabbits twice, in random sequence with and without the concurrent administration of probenecid. Oxprenolol enantiomers were determined in plasma and urine by an enantioselective HPLC method. Oxprenolol glucuronides were measured in plasma and urine after enzymatic hydrolysis. Results. The disposition of the oxprenolol enantiomers in rabbits is stereoselective, mainly due to a difference in metabolism. Renal excretion is only a minor elimination route for unchanged oxprenolol, and the renal clearances of the enantiomers are similar. Pre-treatment with probenecid did not affect the plasma concentrations of the oxprenolol enantiomers, but there was a slight decrease in their urinary excretion. The plasma concentrations of the oxprenolol glucuronides are much higher than those of the parent enantiomers, and those of (S)-glucuronide are about twice those of its antipode. About 10% of the oxprenolol dose is excreted in the urine as glucuronides. The renal clearances of both glucuronides are similar, and markedly higher than the creatinine clearance. After probenecid, the mean glucuronide plasma levels were markedly higher, with for both glucuronides a more than twofold increase in mean AUC. Probenecid decreased the renal clearance of both glucuronides to about 30%. Moreover, it decreased slightly the formation clearance of (S)-glucuronide, while the formation clearance of (R)-glucuronide was not significantly influenced. Conclusions. Our results show that in the rabbit, both oxprenolol glucuronide diastereomers are actively secreted by the kidney, and that this process is inhibited by probenecid.
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    URL: http://dx.doi.org/10.1023/A:1016204309083
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    Microdialysis Sampling to Determine the Pharmacokinetics of Unbound SDZ ICM 567 in Blood and Brain in Awake, Freely-Moving Rats (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 291-294 
    Details
    ISSN: 1573-904X
    Keywords: brain microdialysis ; blood microdialysis ; pharmacokinetics ; free drug concentration ; SDZ ICM 567
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The free concentrations of the serotoninergic 5-HT3 antagonist SDZ ICM 567 in blood and in the central nervous system were examined in awake, freely-moving rats using blood and brain microdialysis coupled to liquid chromatography. Microdialysis probes were implanted in the jugular vein and in the frontal cortex and dialysis samples were simultaneously collected from both sites. Pharmacokinetic parameters were calculated after a 10 mg/kg intravenous dose of [14C]SDZ ICM 567. The elimination half lives measured in whole blood, brain and blood microdialysates were similar (≃1.7 h). The AUC0–5h corresponding to the unbound drug was 462 ± 142 ng · ml−1 · h in blood dialysate, not significantly different from the AUC corresponding to the free concentration in whole blood, i.e. 586 ± 63 ng · ml−1 h. The free fraction in blood obtained in vitro by equilibrium dialysis (21%) or by microdialysis (19%) was not statistically different from that obtained in vivo (17%) in microdialysis experiments. The unbound concentrations (AUC0–5h) of SDZ ICM 567 in the brain cortex were 86 ± 24 ng · ml−l - h, lower than those expected from unbound blood concentrations, suggesting an active transport out of the central nervous system. Finally, microdialysis sampling allowed the determination of pharmacokinetic parameters of SDZ ICM 567 in blood and brain as well as the estimation of the free fraction of drug in blood.
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    URL: http://dx.doi.org/10.1023/A:1016247413935
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    The Influence of Regional Deposition on the Pharmacokinetics of Pulmonary-Delivered Human Growth Hormone in Rabbits (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 356-359 
    Details
    ISSN: 1573-904X
    Keywords: growth hormone ; pulmonary ; pharmacokinetics ; gamma scintigraphy ; drug delivery ; rabbit
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pulmonary deposition and pharmacokinetics of human growth hormone (hGH), administered by aerosol and instillate, in formulations containing 99mTc-DTPA (for gamma scintigraphic imaging) have been studied in five male New Zealand White rabbits. Gamma scintigraphy indicated that the peripheral:central deposition tended to be greater for aerosol (1.54) than for instillate (0.8). Two gamma scintigraphic methods were used to quantify dose deposited by aerosol, which permitted bioavailabilities to be determined. The bioavailable fraction for aerosolized hGH (45%) was greater than for instilled hGH (16%). This was attributed to the differential effects of mucociliary clearance. Absorption rate limited pharmacokinetics prevailed for both hGH formulations with post-peak half-lives approximately 10-fold greater than the intravenous elimination half-life of 40 min. Apparent absorption rate constants resulting from instillation and aerosolization were equivalent (0.0012 min−1and 0.0020 min−1respectively), however lung-to-blood transfer rate constants for aerosol delivery (0.00071 min −l) were greater than for instillation (0.00018 min−1).
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    Pharmacokinetic/Pharmacodynamic Evaluation of Deflazacort in Comparison to Methylprednisolone and Prednisolone (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1096-1100 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; pharmacodynamics ; corticosteroids ; metabolites ; prodrug
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The pharmacokinetics and pharmacodynamics of deflazacort after oral administration (30 mg) to healthy volunteers were determined and compared with those of 20 mg of methylprednisolone and 25 mg of prednisolone. Methods. Methylprednisolone, prednisolone and the active metabolite of deflazacort, 21-desacetyldeflazacort, were measured in plasma using HPLC. For the assessment of pharmacodynamics, differential white blood cell counts were obtained over 24 hours. An integrated pharmacokinetic-pharmacodynamic (PK-PD) model was applied to link corticosteroid concentrations to the effect on lymphocytes and granulocytes. Results. Deflazacort is an inactive prodrug which is converted rapidly to the active metabolite 21-desacetyldeflazacort. Maximum concentrations of 21-desacetyldeflazacort averaged 116 ng/ml and were observed after 1.3 h. The average area under the curve was 280 ng/ml · h, and the terminal half-life was 1.3 h. 21-Desacetyldeflazacort was cleared significantly faster than both methylprednisolone and prednisolone. The PK-PD-model was suitable to describe time course and magnitude of the observed effects. The results were consistent with reported values for glucocorticoid receptor binding affinities for the investigated compounds. Conclusions. Due to the short pharmacokinetic half-life of its active metabolite, pharmacodynamic effects of deflazacort are of shorter duration than those of methylprednisolone and prednisolone. The PK-PD model allows good prediction of pharmacodynamic effects based on pharmacokinetic and receptor binding data.
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    Liposomal Formulations of Cyclosporin A: Influence of Lipid Type and Dose on Pharmacokinetics (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1189-1198 
    Details
    ISSN: 1573-904X
    Keywords: cyclosporins ; liposomal membranes ; lipid dose ; rat ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Liposomal formulations of Cyclosporin A (CyA)3 have been described in more than 30 publications to substitute Cremophor EL (CrEL), a triricinoleate ester of ethoxylated glycerol, as drug carrier. However, conflicting reports did not allow to draw consistent conclusions about the influence of liposomes on CyA pharmacokinetics (PK) and pharmacodynamics. Methods. A series of liposomal CyA-formulations with varying liposome composition and lipid dose but constant CyA dose was compared in rats. Data were analysed with a PK-model taking into account the varying volume of distribution with the varying lipid concentration in blood. Results. Surface properties and lipid type of liposomes are not important PK predictors of liposomal CyA, at least for small dosages of liposomes. Rather, the absolute lipid amount and the lipophilicity of cyclosporins are critical factors influencing the PK of liposomal CyA. The higher the concentration of lipid in blood and the greater the lipophilicity of cyclosporin is, the higher are the concentrations of CyA in blood. Conclusions. These relations may explain the inconsistent literature results. Together with earlier observations from our group the above findings indicate, that CyA is not caged in the liposomal membranes. Reports in literature, which claim lower clearance and a lower volume of distribution of CyA in obese rats compared to lean rats, support our assumption about the involved mechanisms. A semi-quantitative model of CyA distribution is presented, which points to the variable free fraction of CyA in plasma as the crucial factor for all previously reported phenomena in liposomal CyA formulations.
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    Lumping of Whole-Body Physiologically Based Pharmacokinetic Models (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 21-46 
    Details
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; whole body physiologically based model ; lumping ; system theory ; barbiturates
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Lumping is a common pragmatic approach aimed at the reduction of whole-body physiologically based pharmacokinetic (PBPK) model dimensionality and complexity. Incorrect lumping is equivalent to model misspecification with all the negative consequences to the subsequent model implementation. Proper lumping should guarantee that no useful information about the kinetics of the underlying processes is lost. To enforce this guarantee, formal standard lumping procedures and techniques need to be defined and implemented. This study examines the lumping process from a system theory point of view, which provides a formal basis for the derivation of principles and standard procedures of lumping. The lumping principle in PBPK modeling is defined as follows: Only tissues with identical model specification, and occupying identical positions in the system structure should be lumped together at each lumping iteration. In order to lump together parallel tissues, they should have similar or close time constants. In order to lump together serial tissues, they should equilibrate very rapidly with one another. The lumping procedure should include the following stages: (i) tissue specification conversion (when tissues with different model specifications are to be lumped together); (ii) classification of the tissues into classes with significantly different kinetics, according to the basic principle of lumping above; (iii) calculation of the parameters of the lumped compartments; (iv) simulation of the lumped system; (v) lumping of the experimental data; and (vi) verification of the lumped model. The use of the lumping principles and procedures to be adopted is illustrated with an example of a commonly implemented whole-body physiologically based pharmacokinetic model structure to characterize the pharmacokinetics of a homologous series of barbiturates in the rat.
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    URL: http://dx.doi.org/10.1023/A:1023272707390
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    Population Pharmacokinetic Analysis of Mizolastine and Validation from Sparse Data on Patients Using the Nonparametric Maximum Likelihood Method (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 133-161 
    Details
    ISSN: 1573-8744
    Keywords: mizolastine ; pharmacokinetics ; population analysis ; zero-order absorption ; heteroscedastic variance ; NPML ; validation ; predictive distributions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A population analysis of the kinetics of mizolastine was performed from concentrations on 449 allergic patients, using the nonparametric maximum likelihood method (NPML). A two-compartment open model with zero-order absorption was used to describe the kinetics of mizolastine after oral administration. A heteroscedastic variance model was assumed for the error. To explain the kinetic variability, eight covariates were introduced in the analysis: gender, pharmaceutical dosage form, age, body weight, serum creatinine concentration, creatinine renal clearance, plasma levels of hepatic transaminases ASAT and ALAT. Their relationships to the kinetic parameters were studied by means of the estimated distribution of each kinetic parameter conditional on different levels of each covariate. An important interindividual kinetic variability was found for all parameters. Moreover, several kinetic parameters among which the duration of absorption were found to be influenced by pharmaceutical dosage form and gender. Body weight and creatinine renal clearance were found to have a little influence on the oral clearance and the smallest disposition rate constant. This population analysis was validated on a separate group of 247 other patients. For each observed concentration of this sample, a predictive distribution was computed using the individual covariates. Predicted concentrations and standardized prediction errors were deduced. The mean and variance of the standardized prediction errors were, respectively, 0.21 and 2.79. Moreover, in the validation sample, the predicted cumulative distribution function of each observed concentration was computed. Empirical distribution of these values was not significantly different from a uniform distribution, as expected under the assumption that the population model estimated by NPML is adequate.
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    Rapid Attainment of Steady State Plasma Drug Concentrations Within Precise Limits (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 319-328 
    Details
    ISSN: 1573-8744
    Keywords: anesthetic techniques ; continuous infusion ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We describe a method of rapidly obtaining a specified steady state plasma concentration of an intravenous drug within precise limits. The technique requires an initial bolus to raise the plasma concentration to the upper limit followed by a series of constant-rate infusions each of which is associated with a minimum plasma concentration equal to the tower limit. The infusion rate is stepped down when the plasma concentration returns to the upper limit. Computer simulation, based on the method, is used to generate plasma concentration–time curves with fluctuations of up to 10% about selected steady state concentrations of amrinone, esmolol, lidocaine, midazolam, propofol, and theophylline. The utility of this general approach to intravenous dosing and potential limitations of the method are discussed.
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    URL: http://dx.doi.org/10.1023/A:1023285426388
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    Fourth-Generation Model for Corticosteroid Pharmacodynamics: A Model for Methylprednisolone Effects on Receptor/Gene-Mediated Glucocorticoid Receptor Down-Regulation and Tyrosine Aminotransferase Induction in Rat Liver (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 289-317 
    Details
    ISSN: 1573-8744
    Keywords: methylprednisolone ; pharmacokinetics ; pharmacodynamics ; indirect response models ; glucocorticoid receptor ; tyrosine aminotransferase ; Northern hybridization ; mRNA ; down-regulation ; receptor recycling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A fourth-generation pharmacokinetic/pharmacodynamic (PK/PD) model for receptor/genemediated effects of corticosteroids was developed. Male adrenalectomized Wistar rats received a 50 mg/kg iv bolus dose of methylprednisolone (MPL). Plasma concentrations of MPL, hepatic glucocorticoid receptor (GR) messenger RNA (mRNA) and GR density, tyrosine aminotransferase (TAT) mRNA, and TAT activity in liver were determined at various time points up to 72 hr after MPL dosing. Down-regulation of GR mRNA and GR density were observed: GR mRNA level declined to 45–50% of the baseline in 8–10 hr, and slowly returned to predose level in about 3 days; GR density fell to 0 soon after dosing and returned to the baseline in two phases. The first phase, occurring in the first 10 hr, entailed recovery from 0 to 30%. The second phase was parallel to the GR mRNA recovery phase. Two indirect response models were applied for GR mRNA dynamics regulated by activated steroid-receptor complex. A full PK/PD model for GR mRNA/GR down-regulation was proposed, including GR recycling theory. TAT mRNA began to increase at about 1.5 hr, reached the maximum at about 5.5 hr, and declined to the baseline at about 14 hr after MPL dosing. TAT induction followed a similar pattern with a delay of about 1–2 hr. A transcription compartment was applied as one of the cascade events leading to TAT mRNA and TAT induction. Pharmacodynamic parameters were obtained by fitting seven differential equations piecewise using the maximum likelihood method in the ADAPT II program. This model can describe GR down-regulation and the precursor/product relationship between TAT mRNA and TAT in receptor/gene-mediated corticosteroid effects.
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    Third-generation model for corticosteroid pharmacodynamics: Roles of glucocorticoid receptor mRNA and tyrosine aminotransferase mRNA in rat liver (1995)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 23 (1995), S. 163-181 
    Details
    ISSN: 1573-8744
    Keywords: methylprednisolone ; pharmacokinetics ; pharmacodynamics ; glucocorticoid receptor ; tyrosine aminotransferase ; Northern hybridization ; mRNA
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A third-generation pharmacokinetic/pharmacodynamic model was proposed for receptor/genemediated corticosteroid effects. The roles of the messenger RNA (mRNA) for the glucocorticoid receptor (GR) in hepatic GR down-regulation and the mRNA for hepatic tyrosine aminotransferase (TAT) induction by methylprednisolone (MPL) were examined. Male adrenalectomized Wistar rats received 50 mg/kg MPL iv. Blood and liver samples were collected at various time points for a period of 18 hr. Plasma concentrations of MPL, free hepatic cytosolic GR densities, GR mRNA, TAT mRNA, and TAT activities in liver were determined. Plasma MPL profile was biexponential with a terminal t1/2 of 0.57 hr. Free hepatic GR density rapidly disappeared from cytoplasm after the MPL dose and then slowly returned to about 60% of starting level after 16 hr. Meanwhile, GR mRNA level fell to 45% of baseline within 2 hr postdosing, and remained at that level for at least 18 hr. The GR down-regulation of GR mRNA and protein turnover rate were modeled. The TAT mRNA began to increase at about 2 hr, reached a maximum at about 5 hr, and declined to baseline by 14 hr. TAT induction followed a similar pattern, except the induction was delayed about 0.5 hr. Pharmacodynamic parameters were obtained by fitting seven differential equations in a piecewise fashion. The cascade of corticosteroid steps were modeled by a series of inductions for steroid-receptor-DNA complex, two intermediate transit compartments, TAT mRNA, and TAT activity. Results indicate that GR mRNA and TAT mRNA are major controlling factors for the receptor/gene-mediated effects of corticosteroids.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02354270
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    Bayesian design criteria: Computation, comparison, and application to a pharmacokinetic and a pharmacodynamic model (1995)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 23 (1995), S. 101-125 
    Details
    ISSN: 1573-8744
    Keywords: Bayesian designs ; Bayesian estimation ; prior distribution ; pharmacokinetics ; pharmacodynamics ; E max model ; nonlinear models
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In this paper 3 criteria to design experiments for Bayesian estimation of the parameters of nonlinear models with respect to their parameters, when a prior distribution is available, are presented: the determinant of the Bayesian information matrix, the determinant of the preposterior covariance matrix, and the expected information provided by an experiment. A procedure to simplify the computation of these criteria is proposed in the case of continuous prior distributions and is compared with the criterion obtained from a linearization of the model about the mean of the prior distribution for the parameters. This procedure is applied to two models commonly encountered in the area of pharmacokinetics and pharmacodynamics: the one-compartment open model with bolus intravenous single-dose injection and theE max model. They both involve two parameters. Additive as well as multiplicative gaussian measurement errors are considered with normal prior distributions. Various combinations of the variances of the prior distribution and of the measurement error are studied. Our attention is restricted to designs with limited numbers of measurements (1 or 2 measurements). This situation often occurs in practice when Bayesian estimation is performed. The optimal Bayesian designs that result vary with the variances of the parameter distribution and with the measurement error. The two-point optimal designs sometimes differ from the D-optimal designs for the mean of the prior distribution and may consist of replicating measurements. For the studied cases, the determinant of the Bayesian information matrix and its linearized form lead to the same optimal designs. In some cases, the pre-posterior covariance matrix can be far from its lower bound, namely, the inverse of the Bayesian information matrix, especially for theE max model and a multiplicative measurement error. The expected information provided by the experiment and the determinant of the pre-posterior covariance matrix generally lead to the same designs except for theE max model and the multiplicative measurement error. Results show that these criteria can be easily computed and that they could be incorporated in modules for designing experiments.
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    URL: http://dx.doi.org/10.1007/BF02353788
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    A semicompartmental modeling approach for pharmacodynamic data assessment (1995)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 23 (1995), S. 307-322 
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    ISSN: 1573-8744
    Keywords: effect-site link model ; semicompartmental model ; model misspecification ; pharmacokinetics ; pharmacodynamics ; nonlinear regression
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A new method is proposed for modeling the temporal aspects of the pharmacodynamic-pharmacokinetic relationship of drugs. A semicompartmental solution to the effect-site link model of Sheiner et al. (1) formed the basis for this new approach. This semicompartmental solution does not require the specification of a compartmental model for the pharmacokinetic response and may offer an advantage when model misspecification is present in using standard compartmental models. A Monte Carlo simulation study was conducted to evaluate the performance of the semicompartmental modeling approach. This method is easily implemented in standard nonlinear regression packages.
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    URL: http://dx.doi.org/10.1007/BF02354287
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    Optimal Experimental Design for Precise Estimation of the Parameters of the Axial Dispersion Model of Hepatic Elimination (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 595-615 
    Details
    ISSN: 1573-8744
    Keywords: optimal design ; hepatic elimination models ; parameter estimation ; protein binding ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The axial dispersion model of hepatic drug elimination is characterized by two dimensionless parameters, the dispersion number, DN , and the efficiency number, RN , corresponding to the relative dispersion of material on transit through the organ and the relative efficiency of elimination of drug by the organ, respectively. Optimal design theory was applied to the estimation of these two parameters based on changes in availability (F) of drug at steady state for the closed boundary condition model, with particular attention to variations in the fraction of drug unbound in the perfusate (fuB ). Sensitivity analysis indicates that precision in parameter estimation is greatest when F is low and that correlation between RN and DN is high, which is desirable for parameter estimation, when DN lies between 0.1 and 100. Optimal design points were obtained using D-optimization, taking into account the error variance model. If the error variance model is unknown, it is shown that choosing Poisson error model is reasonable. Furthermore, although not optimal, geometric spacing of fuB values is often reasonable and definitively superior to a uniform spacing strategy. In practice, the range of fuB available for selection may be limited by such practical considerations as assay sensitivity and acceptable concentration range of binding protein. Notwithstanding, optimal design theory provides a rational approach to precise parameter estimation.
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    URL: http://dx.doi.org/10.1023/A:1023229318017
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    Single-Dose Pharmacokinetics of Rifapentine in Women (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 75-85 
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    ISSN: 1573-8744
    Keywords: rifapentine ; pharmacokinetics ; gender differences ; female
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Gender can be an important variable in the absorption and disposition of some drugs. In this open-label study, 15 healthy, nonsmoking women received a single 600-mg oral dose of rifapentine. Plasma samples were obtained at frequent intervals for up to 72 hr after the dose to determine the pharmacokinetic (PK) parameters of rifapentine and its active metabolite, 25-desacetyl-rifapentine. Peak plasma rifapentine concentrations (Cmax ) were observed 5.9 hr after ingestion of the single dose. The mean area under the rifapentine plasma concentration–time curve [AUC(0 → ∞ )] was 325 μg · hr ml and the mean elimination half-life (t1/2 ) was 16.3 hr. Plasma concentrations for the 25-desacetyl metabolite peaked at 15.4 hr after the rifapentine dose and declined with a terminal half-life of 17.3 hr. These rifapentine and 25-desacetyl-rifapentine PK data in women were compared to data generated previously in healthy men. Striking similarities in the PK profiles of parent drug and metabolite were found in the two populations. Mean differences in rifapentine CL/F (12%) and t1/2 (2%) were small. The only adverse event reported in the female subjects was discoloration of the urine. Based on these PK and safety data, no dosage adjustments for rifapentine based on gender are recommended.
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    URL: http://dx.doi.org/10.1023/A:1023276808298
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    Pharmacokinetic and Pharmacodynamic Evaluation for Tissue-Selective Inhibition of Cholesterol Synthesis by Pravastatin (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 329-347 
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    ISSN: 1573-8744
    Keywords: HMG-CoA reductase inhibitors ; pravastatin ; tissue-selectivity ; cholesterol synthesis ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The tissue-selective inhibition of cholesterol synthesis by pravastatin was evaluated pharmacokinetically and pharmacodynamically. Plasma, tissue, urine, and bile concentrations were measured after iv bolus injection of pravastatin to rats at various doses. The total body clearance and steady state volume of distribution decreased with increasing dose. A saturable biliary excretion was also observed. The time course of plasma and liver concentrations was described by a three-compartment model, consisting of a central compartment, a deep compartment with an nonsaturable uptake process, and a shallow compartment with saturable uptake and nonsaturable elimination processes. It suggests that a mechanism for the decrease in the total body clearance and distribution volume might be explained by a saturation of pravastatin uptake into the liver. Plasma concentration data after oral administration was also fitted to the same model by connecting an absorption compartment to the shallow compartment. The inhibitory activity of pravastatin against cholesterol synthesis in liver could be related to the concentration in the shallow compartment via a sigmoidal Emax model and the obtained pharmacodynamic parameters were comparable to those in vitro. Results suggest that the carrier-mediated hepatic uptake of pravastatin is actually responsible for the hepatoselective inhibition of cholesterol synthesis under physiological conditions.
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    URL: http://dx.doi.org/10.1023/A:1023237510458
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    Mathematical Formalism and Characteristics of Four Basic Models of Indirect Pharmacodynamic Responses for Drug Infusions (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 385-408 
    Details
    ISSN: 1573-8744
    Keywords: pharmacodynamics ; pharmacokinetics ; indirect response models ; infusions ; inhibition ; stimulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Indirect response models require differential equations to describe the nonlinear inhibition or stimulation of the production or loss (kout ) of the response variable. Partially integrated solutions for these models developed previously for iv bolus or biphasic pharmacokinetics were extended to consider drug infusions for limited or extended durations. Qualitative examination was made of the role of infusion rate and duration, type and rate of drug disposition, Imax or Smax capacity factors, IC50 or SC50 sensitivity factors, and kout values. Properties of the response curves characterized include curve shapes, maximum or minimum response, onset rate, steady-state, and return to baseline. Some comparisons were made with behavior of iv bolus doses. These relationships provide both a formal and practical basis for better understanding of the time-course of basic indirect response models.
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    URL: http://dx.doi.org/10.1023/A:1021060000789
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    Integrated Pharmacokinetic–Pharmacodynamic Model for Acetaminophen, Ibuprofen, and Placebo Antipyresis in Children (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 559-579 
    Details
    ISSN: 1573-8744
    Keywords: acetaminophen ; age ; antipyretic ; fever ; ibuprofen ; pediatrics ; pharmacokinetics ; pharmacodynamics ; temperature
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A descriptive profile for antipyretic drug action has been documented for children. However, a linked pharmacokinetic–pharmacodynamic (PK/PD) model is central to the understanding of antipyretic drug action in febrile children. This was examined for previously reported data from 178 febrile children who received a single oral dose of acetaminophen (APAP) (12.5 mg/kg), ibuprofen (IBU) (5 or 10 mg/kg), or placebo. Rectal temperatures and plasma levels (μg/ml) of APAP and IBU were measured for up to 12 hr after drug administration. Nonlinear regression analyses were applied to these measurements and yielded simultaneous solutions of an integrated one-compartment PK, link, and SigmoidEmax effect model in 102/153 febrile children given APAP or IBU. The PK parameters (tlag ,ka , β,T1 / 2β ,AUC0–∞ ,Vd/F,andClp/F) were not different than those reported previously, except the APAPka was significantly lower. The link component yieldedkeo s of 0.58±0.06 (X±SE), 0.70±0.11 and 0.57 ± 0.11 hr -1 for APAP, IBU05, and IBU10, respectively: the SigmoidEmax component yieldedEC50 s (μg/ml) and sigmoidicity (γ) of 4.63±0.39 and 3.98±0.42 for APAP, 11.33±1.35 and 3.97±0.58 for IBU05 and 12.83±1.89 and 4.27±0.63 for IBU10. On visual inspection of the efficacy–time profiles of the febrile children, a number of them had an apparent linear function (slope; Δ°C/hr) and/or a sinusoidal cyclic function “confounding” standard approaches to PD analysis. Thus, the temperature profiles of 91/102 children given APAP or IBU required the addition of a slope (Δ°C/hr) and/or a sinusoidal cyclic function to the SigmoidEmax component to fit the data satisfactorily. All 22 children given a placebo also required a slope and/or a cyclic function in their PD model. The residual Δ°Cs (observed-predicted) of the placebo group were not significantly different from 0. Thus, no placebo antipyretic effect was observed. Dose dependency of IBUAUC0–∞ was confirmed; doubling the dose from 5 to 10 mg/kg increased theAUC0→∞ by only 1.5-fold. The confounding effect of initial temperature (Tempi ) on antipyretic efficacy in all treatment groups except placebo was also confirmed to expose nonlinear pharmacodynamics. A significant (p=0.03) contribution ofTempi (but not age) on the value of the slope function was found. There was no consistent effect of age orTempi , on the cyclic component of the integrated model of antipyresis. In addition, a multiple linear relationship of age andTempi was observed with a large number of the PK, link, and PD variables in those who received IBU. Dose, age, andTempi interacted with β in a significant multiple linear relationship withAUC0–∞ . The effects of IBU dose, age, andTempi are pervasive and cascade down the chain of events leading to the PD response. The etiology of pyresis may create the slope function, the magnitude of which may be partially due to the underlying disease. In some cases, the cyclic function may be explained by temperature regulation. Regardless of their cause, both confound analysis of drug action and make the simple, unmodified SigmoidEMax effect model less than satisfactory for interpretation of antipyretic drug effects. The influence of Tempi on the magnitude of antipyretic drug response is also a finding with major impact on PD investigations of antipyretic medications. In children receiving IBU, dose and age are also confounders, in addition toTempi . A multiplicity of covariables must be taken into account when developing appropriate dosing regimens for these antipyretics in febrile children.
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    Dose-Dependence and Repeated-Dose Studies for Receptor/Gene-Mediated Pharmacodynamics of Methylprednisolone on Glucocorticoid Receptor Down-Regulation and Tyrosine Aminotransferase Induction in Rat Liver (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 619-648 
    Details
    ISSN: 1573-8744
    Keywords: methylprednisolone ; pharmacokinetics ; pharmacodynamics ; indirect pharmacodynamic response models ; glucocorticoid receptor ; Northern hybridization ; mRNA ; down-regulation ; tyrosine aminotransferase ; dose dependence ; tolerance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Dose-dependent and repeated-dose effects of methylprednisolone (MPL) on down-regulation of glucocorticoid receptor messenger RNA (GR mRNA) and GR density, as well as tyrosine aminotransferase (TAT) mRNA and TAT induction by receptor/gene-mediated mechanisms in rat liver were examined. A previously developed pharmacokinetic/pharmacodynamic (PK/PD) model was used to design these studies which sought to challenge the model. Three groups of male adrenalectomized Wistar rats received MPL by iv injection: low-dose (10 mg/kg at Time 0), high-dose (50 mg/kg at Time 0), and dual-dose (50 mg/kg at Time 0 and 24 hr). Plasma concentrations of MPL, and hepatic content of free GR, GR mRNA, TAT mRNA, and TAT activity were determined. The P-Pharm program was applied for population analysis of MPL PK revealing low interindividual variation in CL and Vc values (3–14%). Two indirect response models were applied to test two competing hypotheses for GR mRNA dynamics. Indirect Pharmacodynamic Response Model I (Model A) where the complex in the nucleus decreases the transcription rate of GR mRNA better described GR mRNA/GR down-regulation. Levels of TAT mRNA began to increase at 1–2 hr, reached a maximum at 5–6 hr, and declined to the baseline at 12–14 hr after MPL dosing. The induction of TAT activity followed a similar pattern with a delay of about 1–2 hr. The low-dose group had 50–60% of the TAT mRNA and TAT induction compared to the high-dose group. Since the GR density returned to about 70% of the baseline level before the second 50 mg/kg dose at 24 hr, tolerance was found for TAT mRNA/TAT induction where only 50–60% of the initial responses were produced. Our fourth-generation model describes the dose dependence and tolerance effects of TAT mRNA/TAT induction by MPL involving multiple-step signal transduction controlled by the steroid regimen, free GR density, and GR occupancy. This model may provide the foundation for studying other induced proteins or enzymes mediated by the similar receptor/nuclear events.
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    URL: http://dx.doi.org/10.1023/A:1020746822634
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    Characterization of Pharmacodynamic Recession Slopes for Direct and Indirect Response Models (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 409-436 
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    ISSN: 1573-8744
    Keywords: pharmacodynamic recession slope ; Hill function ; k · m product ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Direct pharmacologic effects are known to recede over time with largely linear slopes (Levy's k · m product, J. Pharm. Sci. 53: 342, 1964) and indirect responses have similar behavior. Pharmacodynamic slope properties were examined mathematically for the Hill function with monoexponential drug disposition and simulations were carried out for other pharmacokinetic functions. Both types of pharmacodynamic profiles exhibit a single terminal inflection point (fp) when drug concentrations exceed the EC50 (that concentration causing one-half maximum effect, Emax ). For direct effects it was found that Cfp (the drug concentration at fp) =EC50 , the determinants of inflection time were identified, and Slopefp = −λzγEmax /4 where λz is the terminal disposition slope and γ is the Hill coefficient. These characteristics were explored for the four basic indirect response models which also exhibit recession profiles with slight sigmoidity and a single terminal inflection point at higher doses. The drug concentration at inflection Cfp is ≤IC50 or SC50 (drug concentrations causing half-maximal inhibition or stimulation), while the inflection response (Rfp ) attains constant values at larger doses. Indirect Response Models I, III, and IV have nearly linear return slopes for a wide range of doses which are governed by the disposition slope λz of the drug, loss constant kout of the response, maximum inhibition (Imax ) or stimulation (Smax ) factors, and a unique fractional constant (0〈G≤1). Model II exhibits more complex behavior with recession slopes which are less likely to be parallel for various doses. Most indirect responses are expected to show nearly linear recession slopes which are parallel for moderate to large doses and mainly governed by an identical combination of pharmacokinetic (λz ), system (kout ), and dynamic capacity factors (Imax or Smax ).
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    Effects of Intestinal and Hepatic Metabolism on the Bioavailability of Tacrolimus in Rats (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1609-1613 
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    ISSN: 1573-904X
    Keywords: tacrolimus ; bioavailability ; metabolism ; intestine ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Tacrolimus, an immunosuppressive agent, has poor and variable bioavailability following oral administration in clinical use. We investigated the contribution of intestinal metabolism to the first pass effect of tacrolimus in rats. Methods. Tacrolimus was administered intravenously, intraportally or intraintestinally to rats. Blood samples were collected over a 240-min period, and blood tacrolimus concentrations were measured. The extraction ratios of tacrolimus in the intestine and liver were investigated. In addition, the metabolism of tacrolimus in the everted sacs of the small intestine was examined. Results. The rate of absorption of tacrolimus in the intestine was rapid, and tacrolimus was almost completely absorbed after intestinal administration. The bioavailability of tacrolimus was about 40% and 25% after intraportal and intraintestinal administration, respectively, indicating that tacrolimus is metabolized in both the intestine and the liver. In addition, tacrolimus was significantly metabolized in the everted sacs of the rat intestine. Conclusions. The present study suggested that the metabolism of tacrolimus in the intestine contributes to its extensive and variable first pass metabolism following the oral administration.
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    Pharmacokinetics and Anticonvulsant Effect of a New Hypnotic, CL 284,846, in Rats (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1592-1597 
    Details
    ISSN: 1573-904X
    Keywords: anticonvulsant ; CL 284,846 ; CL 284,859 ; pentylenetetrazol ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. CL 284,846 (CL846) is an investigational non-benzodiazepine agent with hypnotic, anxiolytic, myorelaxant and anticonvulsant properties. This study assessed the pharmacokinetics and anticonvulsant action of CL846 in female Sprague-Dawley rats. Methods. CL846 pharmacokinetics were examined after either an iv bolus dose (2.5 mg/kg) or a 6-hr infusion (0.4 mg/kg/hr). CL846 pharmacodynamics were evaluated with a pentylenetetrazol (PTZ) infusion 5 min after a CL846 in bolus dose (0 to 10 mg/kg). CL846 and the derived metabolite CL 284,859 (CL859) concentrations in serum and brain tissue were determined by HPLC with fluorescence detection. Results. Both the steady-state volume of distribution (1636 ± 162 and 1804 ± 293 ml/kg, after bolus and infusion administration, respectively) and systemic clearance (19.1 ± 7.1 and 22.2 ± 4.3 ml/min/kg for bolus and infusion administration, respectively) were high. No differences in pharmacokinetic parameters were noted between the two modes of administration. The relationship between anticonvulsant effect and brain/serum concentrations was well described by an Emax model. CL846 was as effective as triazolam in antagonizing PTZ-induced seizures. Conclusions. Under the conditions of the present study, CL846 pharmacokinetics were linear and stationary. Further evaluation of the anticonvulsant properties of CL846 is warranted, including the potential development of tolerance, which is well known for benzodiazepines.
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    URL: http://dx.doi.org/10.1023/A:1016224629614
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    MicroPharm-K, a Microcomputer Interactive Program for the Analysis and Simulation of Pharmacokinetic Processes (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1225-1230 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; nonlinear minimisation ; computer program ; software ; estimation ; simulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The microcomputer program, MicroPharm-K (MP-K) was developed for pharmacokinetic modeling, including analysis of experimental data and estimation of relevant parameters, and simulation. The intention was to provide a user-friendly, interactive, event-driven program for PC computers. Methods. The data are ascribed to a predefined model from a library including various routes of administration, oral or intra-venous, bolus or infusion, and various compartmental interpretations, 1 to 3. Single and multiple administrations are supported. The program provides initial estimates of the parameters in most cases, and the parameters are then fitted to the model by non linear model fitting using either the Simplex, Evol, Gauss-Newton, Levenberg-Marquardt or Fletcher-Powell algorithms. The non linear model fitting is based on the maximum likelihood method, and the criterion to minimize is either the weighted least squares (Chi2 criterion) or the extended least squares. Graphical representations of non-fitted or curve-fitted data are immediately available (including log-scale representation), as well as pharmacokinetic typical parameters such as area under the curve, clearance, volumes, time-rate constants, transfer rate constants, etc. Results. Simulated and experimental data were analysed and the results were similar to those obtained by other programs. Conclusions. This non linear fitting program has been proved in our laboratory to be a very effective package for pharmacokinetic studies, including estimation and simulation. Because it is easy-to-use and runs on basic computers, the program could also be used for educational purposes.
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    URL: http://dx.doi.org/10.1023/A:1016280430580
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    Absorption and Presystemic Metabolism of Nefazodone Administered at Different Regions in the Gastrointestinal Tract of Humans (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1716-1721 
    Details
    ISSN: 1573-904X
    Keywords: nefazodone ; site of absorption ; intubation ; pharmacokinetics ; P450 metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The absorption and disposition of nefazodone (NEF) and its metabolites hydroxynefazodone (HO-NEF), m-chlorophenylpiperazine (mCPP) and triazole dione (dione) were assessed in 10 healthy subjects following infusion of NEF solution into the proximal and distal regions of the intestine vs administration of NEF solution orally by mouth. Methods. NEF HC1 (400 mg) was infused over 5 hours into the proximal or distal intestine through a nasogastric tube, or orally ingested in 10 divided doses over 4.5 hours. The three treatments in the three-period crossover design were separated by one week. Results. The bioavailability of NEF, based on AUC(INF), from proximal and distal regions relative to that from oral administration was 97% and 106%, respectively. NEF was absorbed equally well from all three treatments with median Tmax of 5.0 hours which coincided with the duration of infusion. Mean Cmax of NEF was not different between proximal and oral administrations, however, mean Cmax after distal instillation was 40% lower than that after oral administration. Exposure to HO-NEF, mCPP and dione, following proximal instillation was also comparable to that after oral administration. AUC(INF) of HO-NEF and dione was significantly lower after distal instillation compared to that after oral administration but AUC(INF) of mCPP was not. Cmax of all metabolites was significantly lower after distal administration in comparison to oral treatment. Terminal half-life for NEF, HO-NEF and mCPP after distal administration was longer than the other two treatments. Conclusions. NEF is absorbed throughout the length of the gastrointestinal tract which supports the development of an extended-release formulation of NEF. The exposure to the metabolites (relative to NEF) was lower from the distal intestinal site compared to the proximal and oral site which may be explained by a reduced first pass of NEF by the cytochrome P450 3A4 in the distal intestine.
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    Contribution of Parenchymal and Non-Parenchymal Liver Cells to the Clearance of Hepatocyte Growth Factor From the Circulation in Rats (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1737-1740 
    Details
    ISSN: 1573-904X
    Keywords: hepatocyte growth factor ; receptor-mediated endocytosis ; pharmacokinetics ; liver
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The distribution of 125I-hepatocyte growth factor (HGF) to either liver parenchymal cells (PC) or non-parenchymal cells (NPC) was investigated in rats. Methods. After injection of a trace amount of 125I-HGF, the distribution of radioactivity determined by microautoradiography closely resembled that of 125I-epidermal growth factor which distributes mainly to PC. Results. The uptake clearance of 125I-HGF estimated by determining the radioactivity of isolated liver cells was three times higher for PC than for NPC. This suggests that HGF distributes mainly to PC at relatively low doses. On the other hand, the uptake clearance by PC fell on coadministering an excess (80 µg/kg) of unlabeled HGF, while no change was observed for NPC, indicating that a saturable process for the hepatic handling of HGF exists only in PC where the HGF receptor is expressed. Conclusions. At such a dose the uptake clearance was comparable for both PC and NPC showing that HGF distributes to both cell types although NPC have few HGF receptors. Since the distribution to NPC was relatively non-specific and heparin-sensitive, it may be that heparin-like substances, which are believed to exist on PC and/ or the extracellular matrix, also exist on NPC.
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    The Problem of Racemization in the Stereospecific Assay and Pharmacokinetic Evaluation of Ketorolac in Human and Rats (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1652-1657 
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    ISSN: 1573-904X
    Keywords: ketorolac ; racemization ; inversion ; stereospecific assay ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. A comparison of a previously reported indirect (precolumn derivatization) assay for ketorolac (KT) and a new direct method described here was made to establish the conditions under which KT may undergo racemization and to explain the observed discrepancies in the pharmacokinetics of KT reported in the literature. Methods. A previously reported pre-column derivatization method and a new direct method were employed to determine the effect of pH and ionic strength on racemization. Using the conditions where no racemization occurred, the pharmacokinetics in humans and rats, and protein binding of KT enantiomers were determined. Results. Under the chromatographic conditions employed for the direct assay, no racemization was observed. Under high pH and ionic strength, however, both methods resulted in KT racemization. The indirect method resulted in rapid and complete racemization due to the strong basic conditions required for derivatization. In both humans and rats, the pharmacokinetics of racemic KT were stereoselective with the R enantiomer being predominant (AUC S/R: humans, 0.26; Rats: 0.45). This is likely due to more extensive plasma protein binding of S than its antipode (unbound S/R: 1.35). Conclusions. The discrepancies in the literature may be explained by rapid racemization of KT that occurs during sample preparation for the pre-column derivatization method. Considerations should be given to the possibility of racemization during the assay development and validation.
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    Prolonged Circulation of Recombinant Human Granulocyte–Colony Stimulating Factor by Covalent Linkage to Albumin Through a Heterobifunctional Polyethylene Glycol (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1883-1888 
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    ISSN: 1573-904X
    Keywords: albumin ; granulocyte-colony stimulating factor ; polyethylene glycol ; protein conjugate ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Recombinant human granulocyte-colony stimulating factor (rhG-CSF) was covalently conjugated to both rat and human serum albumin (RSA and HSA respectively) to increases the circulating half life (t1/2) of rhG-CSF. Methods. Conjugates of RSA (MW 67,000) and HSA (MW 66,000) were prepared by linking the two proteins through a heterobifunctional maleimido-carboxyl polyethylene glycol (PEG) and were tested in the rat. The conjugates were injected intravenously (IV) at the equivalent dose of 50 µg/kg of rhG-CSF, and white blood cell (WBC) counts and plasma concentrations of drug were determined. A comparison of pharmacokinetic parameters was made between rhG-CSF, the conjugates RSA-PEG-rhG-CSF and HSA-PEG-rhG-CSF, and a non-covalent mixture of rhG-CSF and HSA. Results. The albumin-rhG-CSF conjugates are eliminated more slowly from the circulation. The clearance values are reduced from 0.839 ± 0.121 ml/mm/kg for rhG-CSF to 0.172 ± 0.013 ml/min/kgfor RSA-PEG-rhG-CSF and 0.141 ± 0.005 ml/mm/kg for HSA-PEG-rhG-CSF. WBC counts increased in both absolute number and duration as compared to rhG-CSF alone. The albumin rhG-CSF conjugates had enhanced serum stability relative to free rhG-CSF. The rate of degradation of the albumin conjugates incubated in rat serum at 37°C decreased five fold. Conclusions. The results from the study show that specific conjugation of rhG-CSF to albumin decreases plasma clearance in vivo, causes increased WBC response, and increases serum stability as compared to free rhG-CSF.
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    Evidence for the Lack of a Human Metabolic Isotope Effect of a Deuterium Analog of Fluphenazine (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1388-1390 
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    ISSN: 1573-904X
    Keywords: fluphenazine ; stable isotope ; deuterium labeled ; mass spectrometry ; schizophrenics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
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    URL: http://dx.doi.org/10.1023/A:1016298329188
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    Pharmacokinetics of Oral Extended-Release Dosage Forms. I. Release Kinetics, Concentration, and Absorbed Fraction (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 720-728 
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    ISSN: 1573-904X
    Keywords: extended-release ; in vivo release kinetics ; pharmacokinetics ; absorbed fraction ; in vitro/in vivo correlation absorption rate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In this study, we derive pharmacokinetic models for oral extended-release (OER) drug products with defined in vivo release kinetics (IVRK) and a compartmental system. Fitting the model to clinical data, we were able to examine the correlation between released and absorbed fractions. Furthermore, we found that absorbed fractions of OER products can be expressed by absorption rate and release duration only. The expression is unchanged in different compartmental systems with the same IVRK, implying that the IVRK drives the pharmacokinetic system of an OER product. The apparent absorption rate constant of an OER product can be estimated by solving an implicit equation using observed concentrations. We also propose a new method for calculating absorbed fractions, which is more accurate than Loo-Riegelman method. Ultimately, these methods may permit optimally designed OER products.
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    Comprehensive Pharmacokinetics of Urinary Human Follicle Stimulating Hormone in Healthy Female Volunteers (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 844-850 
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    ISSN: 1573-904X
    Keywords: urinary human FSH ; pharmacokinetics ; immunoassay ; in vitro bioassay ; immunoassay:bioassay ratio
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The study determined the pharmacokinetics of urinary human follicle stimulating hormone (u-hFSH) in 12 down-regulated healthy female volunteers. Methods. Following pituitary desensitization, baseline FSH serum levels were measured over a 24-hour period. Then each subject received, in random order, single doses of u-hFSH (Metrodin®), 75 IU, 150 IU and 300 IU iv, and 150 IU im on four occasions separated by washout periods of one week. Blood and urine samples were collected at preset times. FSH levels were measured by a immuno-radiometric assay and an in vitro rat granulosa cells aromatase bioassay. Results. All doses of u-hFSH were well tolerated. After an iv bolus, the pharmacokinetics of FSH were well described by a two-compartment open model. Immunoassay data showed that the total exposure to FSH was proportional to the administered dose. Mean total clearance of FSH was approximately 0.5 L·h−1 and renal clearance was 0.14 L·h−1. The volume of distribution at steady-state was around 8 liters. The distribution half-life was 2 h and the terminal half-life nearly one day. After im injection, almost two thirds of the administered dose was available systemically. The in vitro bioassay confirmed this pharmacokinetic analysis. Conclusions. The estimation of the elimination half-life of around one day indicates that the maximal effect of a given dose of u-hFSH administered daily cannot be observed until 3 to 4 days of repeated administration. This indicates that, on a pure pharmacokinetic basis, physicians should wait at least 4 days to assess the efficacy of a given dose of u-hFSH and that they should not modify dosage too frequently.
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    URL: http://dx.doi.org/10.1023/A:1016204919251
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    Soft Drugs 19. Pharmacokinetics, Metabolism and Excretion of a Novel Soft Corticosteroid, Loteprednol Etabonate, in Rats (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 875-879 
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    ISSN: 1573-904X
    Keywords: soft corticosteroid ; loteprednol etabonate ; pharmacokinetics ; metabolism ; excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Pharmacokinetics, metabolism and excretion of loteprednol etabonate (LE) were investigated in rats. Methods. The pharmacokinetic studies were performed by iv injections of LE (1-20 mg/ kg). In the metabolism and excretion studies, 0.5-10 mg/kg of LE were iv administered, bile and urine samples were collected for 6 hr. Results. The pharmacokinetic of LE showed a rapid, dose-dependent elimination with a total blood clearance (CLtotal) of higher than 60 ml/min/kg. The metabolism and excretion of LE also showed a marked dose-dependency. At 6 hr after iv of LE (0.5-10 mg/kg), the total recoveries (LE and the metabolites, AE & A, in bile and urine) were 99.35-26.72%. However, only about 2% of LE was excreted from the body through the urine. There were 0.93-2.12% and 0.66-0.26% of AE, and 75.67-19.69% and 20.74-2.77% of A excreted in the bile and urine, respectively. The excretion of A was dose dependent, and significantly higher at the lower dose. Using the (% of total excretion) vs. (log dose) plots, it could be predicted that almost all of the administered LE will be metabolized, and excreted as A when the systemic dose is lower than 0.25 mg/kg. Conclusions. The results indicate that LE absorbed systemically, after topical administration, can be rapidly transformed to the inactive metabolites, and eliminated from the body mainly through the bile and urine.
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    Sumatriptan Absorption from Different Regions of the Human Gastrointestinal Tract (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 138-143 
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    ISSN: 1573-904X
    Keywords: sumatriptan ; gastrointestinal tract ; absorption ; metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Sumatriptan exhibits low oral bioavailability partly due to presystemic metabolism, which may vary with regional differences in metabolic activity throughout the gastrointestinal tract. This study evaluated sumatriptan absorption in humans after administration orally and by oroenteric tube into the jejunum and cecum. Because the site of cecal administration varied, pharmacokinetic parameters for sumatriptan and its major metabolite were compared statistically only after oral and jejunal administration. One-half of the oral dose was recovered in the urine as parent (3%) and metabolite (46%). Sumatriptan was absorbed throughout the gastrointestinal tract; absorption was similar after oral and jejunal administration, and less after cecal administration. The metabolite AUC and the AUC ratio (metabolite/parent) were significantly lower after jejunal compared to oral administration; the AUC ratio was two-fold lower after cecal administration. Results suggest that presystemic metabolism of sumatriptan varies throughout the gastrointestinal tract and/or regional differences exist in the absorption of metabolite formed within the gastrointestinal tract.
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    Effect of Norfloxacin on Theophylline Disposition: A Comparison with Other Fluoroquinolones (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 257-262 
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    ISSN: 1573-904X
    Keywords: norfloxacin ; theophylline ; pharmacokinetics ; drug–drug interactions ; ciprofloxacin ; enoxacin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The effects of norfloxacin (NOR), at steady-state plasma concentrations of 0–32 mg · 1−1, on the plasma clearance of a 6 mg · kg-1 iv bolus dose of theophylline (THEO) in the male Sprague-Dawley rat have been studied. The effects were characterised by a Ki value (Ki = 12 µM), which was comparable with Ki values obtained previously under identical conditions for ciprofloxacin, but higher than that obtained for enoxacin. The distributional characteristics, volume of distribution and liver to plasma concentration ratio, were very similar for the three compounds. The only marked pharmacokinetic differences were in hepatic clearance, where there was a rank order NOR 〉 ciprofloxacin 〉 enoxacin, a reverse of the order in the reduction of THEO clearance seen in clinical studies. The advantages of using the steady-state experimental design described here are that equivalent concentrations are utilised to compare related drugs and differences in pharmacokinetics are accounted for, to allow a direct comparison of potency. This information, together with additional pharmacokinetic considerations, suggests that the different effects on THEO clearance seen in the clinic for NOR, ciprofloxacin and enoxacin are not solely due to differences in inhibitory potency, but also involve differences in hepatic clearance and hence systemic availability of the fluoroquinolones.
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    Human Drug Absorption Kinetics and Comparison to Caco-2 Monolayer Permeabilities (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 47-52 
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    ISSN: 1573-904X
    Keywords: permeability ; oral absorption ; Caco-2 cells ; pharmacokinetics ; human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study aims to assess the drug absorption kinetics of three drugs and compare their resulting first-order intestinal permeation rate constants to their Caco-2 monolayer permeabilities. Methods. In vitro dissolution — in vivo absorption analysis was conducted on four formulations of each ranitidine HC1, metoprolol tartrate, and piroxicam to yield apparent and "true” human clinical permeation rate constants. Drug permeability coefficients through Caco-2 monolayers were also determined. Results. In vitro dissolution — in vivo absorption analysis revealed different relative and absolute contributions of dissolution and intestinal permeation to overall drug absorption kinetics for various drug formulations and yielded estimates of each drug's true and apparent human intestinal permeation rate constant [k p = 0.225 hr−1, 0.609 hr−l, and 9.00 hr−1 for ranitidine, metoprolol, and piroxicam, respectively]. A rank order relationship was observed for both the apparent and true permeation rate constant with Caco-2 monolayer permeability. The decrease in the true permeation rate constant relative to the apparent permeation rate constant was most significant (almost three-fold) for the least permeable compound, ranitidine. Conclusions. There were marked differences in the permeation kinetics of ranitidine, metoprolol, and piroxicam. The possibility of an association between absorption kinetics from dosage forms in humans and Caco-2 monolayer permeability may allow for a direct kinetic interpretation of human oral absorption from Caco-2 monolayer permeability values.
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    Rapid Determination of Oral Pharmacokinetics and Plasma Free Fraction Using Cocktail Approaches: Methods and Application (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 93-97 
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    ISSN: 1573-904X
    Keywords: cocktail dosing ; pharmacokinetics ; plasma free fraction ; ultrafiltration ; HPLC/APCI/MS
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To apply cocktail approaches for protein binding (PB) and pharmacokinetics (PK) within a discovery program as a means of providing timely systemic exposure (AUC and Cmax) data. Methods. For PB data, a procedure of cocktail ultrafiltration, mixed matrix sample preparation and single quadrupole atmospheric pressure ionization LC/MS analysis was used. In vivo PK studies consisted of 4 experimental compounds and a control compound dosed orally at 1 mg/kg (5 mg/kg total dose), with plasma samples obtained at 0.5, 1, 2, 4 and 8 h post dose. For PB and in vivo PK analysis, a control compound was tested within each cocktail to ensure consistent reproducibility. Results. Approximately 2 weeks were spent comparing single and cocktail approaches to determine the feasibility of this method for this project. Comparisons of cocktail data with single compound data revealed no significant differences between the approaches. The oral AUC values ranged from 0.01 to 9.28 μg⋅hr/ml and the Cmax values ranged from 0.04 to 2.17 μg/ml. Free fractions of the 44 compounds studied ranged from 0.006 to 0.271. Using the free fraction values to correct for free AUC and Cmax results in ranges of 0.001 to 0.473 μg⋅hr/ml, and 0.001 to 0.119 μg/ml, respectively. Conclusions. All 44 compounds tested had similar potencies in vivo. Thus, these results suggest that a respective 400 and 100-fold range in AUC and Cmax corrected for free fraction exist in the presence of comparable in vivo activity. The ability to generate this type of data in a timely manner allowed the selection of a candidate with low peripheral exposure relative to the effective dose. The free fraction and PK data on the 44 compounds described was collected within three work days by 2 lab scientists.
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    Elucidation of Human Amphotericin B Pharmacokinetics: Identification of a New Potential Factor Affecting Interspecies Pharmacokinetic Scaling (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1630-1636 
    Details
    ISSN: 1573-904X
    Keywords: amphotericin B ; pharmacokinetics ; human ; gender-differences ; disposition function differences ; interspecies scaling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To elucidate the pharmacokinetics of amphotericin B in rats, mice and humans, and to perform interspecies scaling to humans using allometry. Methods. Plasma concentrations following intravenous bolus administration in rats, and mice were determined by HPLC. Human pharmacokinetic parameters elucidated from literature data were validated in a preliminary study involving a patient receiving daily infusion dose for 27 days. A critical literature review was conducted to identify appropriate pharmacokinetic parameter values in other species for interspecies scale-up. Interspecies allometric scale-up was performed across mice, rats, rabbits and dogs and the resulting predictions in humans were compared to observed values. Results. A triexponential decline in rat, mouse and human plasma concentrations were observed. No gender differences in rat pharmacokinetics were observed. In contrast to allometry, mouse CL was smaller (82 vs 116 ml/h/kg) and T0.5 (33 vs 20 h) was longer compared to rat. In the preliminary human study, Cpeak and Cmin values remained relatively constant over the duration of therapy, and a CL, MRT, T0.5, Vss and Vdarea of 26 ml/h/kg, 10 and 23 days, 6.2 and 20 L/kg, respectively, were estimated. The relative contributions of the terminal phase area in rat, mouse and human were 75%, 92% and 31%, respectively. Interspecies allometric scale-up predictions of human CL (41 ml/h/kg), CLu (467 ml/h/kg) and Vss (3.3 L/kg) were similar to reported values, whereas poor predictions of human Vuss (33 L/kg), Vdarea (4.1 L/kg) and T0.5 (3 days) were obtained. Conclusions. Insignificant accumulation in humans inspite of the long terminal T0.5 was rationalized to be due to the small terminal-phase area contribution. While human CL and Vss were sucessfully predicted in the interspecies scaling, poor predictions of human Vdarea and T0.5 were obtained, which was attributed to disposition pattern differences between humans and other species, a potential new critical factor affecting interspecies scale-up.
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    Pharmacokinetics of 1 -(2-Deoxy-2-fluoro-β-L-arabino-furanosyl)-5-methyluracil (L-FMAU) in Rats (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1350-1353 
    Details
    ISSN: 1573-904X
    Keywords: l-(2-deoxy-2-fluoro-β-L-arabinofuranosyl)-5-methyluracil ; L-FMAU ; nucleoside ; pharmacokinetics ; hepatitis B virus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The objective of this study was to characterize the pharmacokinetics of 1 -(2-deoxy-2-fluoro-β-L-arabinofuranosyl)-5-methyluracil (L-FMAU), a nucleoside analogue with potent activity against the hepatitis B virus and the Epstein-Barr virus, in rats. Methods. Three doses of L-FMAU were administered intravenously (10, 25, and 50 mg/kg) to rats, and L-FMAU concentrations in plasma and urine were measured by HPLC. Pharmacokinetic parameters were generated by using area-moment analysis. Results. There were no significant differences in the pharmacokinetic parameters between the three doses (α 〈 0.05). Thus, the disposition of L-FMAU was linear over the dosage of 10 to 50 mg/kg. Plasma concentrations of L-FMAU declined rapidly with a terminal phase half-life of 1.33 ± 0.45 h (mean ± SD). Total clearance of L-FMAU was moderate, averaging 1.15 ± 0.28 L/h/kg. The fraction of compound excreted unchanged in urine was 0.59 ± 0.13. No glucuronide metabolite was found in the urine. The steady-state volume of distribution was 1.12 ± 0.26 L/kg indicating intracellular distribution of the compound. The fraction of L-FMAU bound to plasma proteins was approximately 15% and was independent of nucleoside concentration. Conclusions. The pharmacokinetics of L-FMAU in rats were independent of dose over the dosage range of 10 to 50 mg/kg.
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    Use of Parent Drug and Metabolite Data in Bioavailability Assessment of a Novel Diltiazem HC1 Once-Daily Product (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 2071-2074 
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    ISSN: 1573-904X
    Keywords: absorption rate ; bioavailability ; bioequivalence ; diltiazem ; metabolites ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016241317260
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    Pharmacokinetic Study of Zeolite A, Sodium Aluminosilicate, Magnesium Silicate, and Aluminum Hydroxide in Dogs (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 270-274 
    Details
    ISSN: 1573-904X
    Keywords: Zeolite A ; silicon ; aluminum ; bioavailability ; pharmacokinetics ; sodium aluminosilicate ; magnesium trisilicate ; aluminum hydroxide ; dog
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Zeolite A is a synthetic zeolite which may have therapeutic utility in osteoporotic individuals because of its ability to stimulate bone formation. A study of Zeolite A (30 mg/kg), sodium aluminosilicate (16 mg/kg), magnesium trisilicate (20 mg/kg), and aluminum hydroxide (675 mg) was designed in beagle dogs. The purpose of this study was to compare the oral bioavailability of silicon and aluminum from Zeolite A, sodium aluminosilicate, magnesium trisilicate, and aluminum hydroxide in dogs. Twelve female dogs received each compound as a single dose separated by one week in a randomized, 4-way, crossover design. Plasma samples were drawn at time 0 and for 24 hours after dosing. The concentrations of silicon and aluminum were determined by graphite furnace atomic absorption. The mean plasma silicon AUC values (±S.D.) were 9.5 ± 4.5, 7.7 ± 1.6, 8.8 ± 3.0, 6.1 ± 1.9 mg · hr/L and the mean plasma silicon Cmax values (±S.D.) were 1.07 ± 1.06, 0.67 ± 0.27, 0.75 ± 0.31, 0.44 ± 0.17 mg/L for Zeolite A, sodium aluminosilicate, magnesium trisilicate, and aluminum hydroxide respectively. Although mean silicon AUC and Cmax values were elevated when compared to baseline after administration of the silicon containing compounds, only the AUC from Zeolite A reached statistical significance (p = 0.041). The mean plasma silicon Tmaxvalues (±S.D.) were 7.9 ± 6.4, 5.8 ± 4.6, 6.9 ± 6.3 and 8.5 ± 3.4 hrs for Zeolite A, sodium aluminosilicate, magnesium trisilicate and aluminum hydroxide respectively. These values were not statistically different. The mean plasma aluminum AUC values for Zeolite A, sodium aluminosilicate, magnesium trisilicate and aluminum hydroxide (±S.D.) were 342 ± 111, 338 ± 167, 315 ± 69, 355 ± 150 µg · hr/L and the mean aluminum Cmax values (±S.D.) were 29 ± 9, 27 ± 14, 24 ± 5 µg/L, 29 ± 11 respectively. The plasma aluminum Tmax values (±S.D.) were 3.5 ± 4.1, 4.2 ± 4.3, 5.7 ± 7.3 and 5.0 ± 4.7 hrs for Zeolite A, sodium aluminosilicate, magnesium trisilicate, and aluminum hydroxide respectively. There was no statistically significant absorption of aluminum from the aluminum containing treatments.
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    Preclinical pharmacokinetics and antitumor activity of imexon (1995)
    Springer
    Investigational new drugs 13 (1995), S. 113-116 
    Details
    ISSN: 1573-0646
    Keywords: Imexon ; pharmacokinetics ; aziridines ; leukemia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Imexon is an aziridine compound originally studied for immune-enhancing effects on lymphocytes. The drug was well-tolerated in humans and was shown to be active in a variety of animal tumor models. Recently, imexon has demonstrated antitumor activity in human multiple myeloma cell linesin vitro. The pharmacokinetics of the compound using a normal phase HPLC assay were studied in normal mice and in dogs with mast cell tumors. Doses of 100 mg/kg given intraperitoneally produced peak plasma levels over 100 (μml in mice and the drug was rapidly eliminated with half lives of 8 minutes (α phase) and 29 minutes (β phase). Only 20% of an oral imexon dose was absorbed in the mouse. In dogs, the α and β phase half lives ranged from 18–26 minutes and 91–110 minutes, respectively. Peak levels over 100 μg/ml were obtained following intravenous doses of 12.5 mg/kg and 25 mg/kg. Imexon was active in mice bearing either P-388 or L-1210 leukemia, but not in mice with B-16 melanoma. These results suggest that cytotoxic drug concentrations can be obtainedin vivo and that imexon is active in lymphoproliferative tumors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00872858
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  • 90
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    A phase I and pharmacokinetic trial of terephthalamidine (NSC 57155) as a 120-hour continuous infusion (1998)
    Springer
    Investigational new drugs 16 (1998), S. 57-67 
    Details
    ISSN: 1573-0646
    Keywords: phase I ; pharmacokinetics ; terephthalamidine ; NSC 57155 ; phthalanilides
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract In this phase I study, terephthalamidine was administered as a 120-hour continuous infusion repeated every 21 days. Thirteen patients received 27 courses of terephthalamidine at four dose levels (14, 28, 46, and 70 mg/m2/day). Dose-limiting toxicity consisted of profound and intractable anorexia, weight loss and prostration in all patients. Toxicity was delayed and accompanied by hyponatremia and hypokalemia. No hematologic or other toxicity was documented. One patient with adenocarcinoma of the lung had a 40% decrease in mediastinal lymph nodes and resolution of a pleural effusion lasting 2 months. Pharmacokinetic analysis by HPLC was performed in all patients during their first course. The harmonic mean terminal half-life for terephthalamidine was 23 hours with a plasma clearance of 1.7 l/hr/m2. Both plasma concentrations achieved during infusion (r2 = 0.9) and area under the curve (AUC) (r2 = 0.8) were proportional to increase in dose (p 〈 0.002). Renal excretion accounted for 64% of the total cumulative dose, with an average renal clearance of 1.16 l/hr/m2. Due to the unacceptable toxicity seen at all doses with this schedule, no further studies are recommended unless the mechanism of toxicity is better understood and can be prevented.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006003718255
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  • 91
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    Effect of Particle Size and Charge on the Disposition of Lipid Carriers After Intratumoral Injection into Tissue-isolated Tumors (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 128-132 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; tissue-isolated tumor ; liposome ; emulsion ; intratumoral injection
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Pharmacokinetic properties of various lipid carriers (liposome and emulsions) after intratumoral injection were studied in perfusion experiments using tissue-isolated tumor preparations of Walker 256 carcinosarcoma. Methods. Four types of lipid carriers, large emulsion (254 nm), small emulsion (85 nm), neutral liposomes (120 nm) and cationic liposomes (125 nm) were prepared. We quantified their recovery from the tumor, leakage from the tumor surface and venous outflow after intratumoral injection into perfused tissue-isolated tumors, and analyzed venous appearance curves based on a pharmacokinetic model. Results. In contrast to the small emulsion and neutral liposomes, which immediately appeared in the venous outflow perfusate following intratumoral injection, the appearance of the cationic liposomes and the large emulsion was highly restricted, clearly demonstrating that intratumoral clearance of these formulations can be greatly retarded by the cationic charge and large particle size, respectively. The venous appearance rate-time profiles were fitted to equations derived from a two-compartment model by nonlinear regression analysis. When the calculated parameters were compared among these four formulations, the venous appearance rate did not exhibit such a large difference; however, the rate of transfer from the injected site to the compartment which involves clearance by venous outflow was all very different. Conclusions. The results of this study indicate that the determining factor which alters the pharmacokinetic properties of these lipid carriers after intratumoral injection is not the rate of transfer from the interstitial space to the vascular side but the rate of intratumoral transfer from the injection site to the well-vascularized region.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011921324952
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  • 92
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    Estimation of Oral Bioavailability of a Long Half-Life Drug in Healthy Subjects (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1782-1786 
    Details
    ISSN: 1573-904X
    Keywords: bioavailability ; pharmacokinetics ; squalene synthase inhibitor ; prodrug
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To estimate and compare the oral bioavailability of a drug (BMS-187745) administered as single doses of oral solution of either the parent drug or its prodrug (BMS-188494). Methods. A single-dose, two-period, three-treatment, control-balanced, residual-effect, incomplete block crossover study was completed in 16 healthy male subjects. All subjects received a 10 mg IV infusion of BMS-187745, and a single oral dose of either BMS-187745 (PO1) or BMS-188494 (PO2). A model is proposed to calculate the oral bioavailability of BMS-187745 which has a long half-life; incomplete data points were available to characterize its elimination phase. The plasma concentration-time data obtained following IV infusion of parent drug, and after administration of either PO1 or PO2 treatment were fitted simultaneously with systemic pharmacokinetic parameters shared by both the oral and IV routes of administration. Results. The best simultaneous fittings of the plasma concentration-time data were obtained by using a biexponential pharmacokinetic model with a first-order absorption rate constant. The mean bioavailability (F) values of BMS-187745 estimated by the proposed model were 26.5% and 2.6% when given as oral solution of its prodrug and as the parent drug. The coefficient of variation (CV) of these F values are reasonable, ranging from 38−40%. In contrast, F calculated by the model-independent AUC method exhibited high CV, ranging from 111−120%. Conclusions. The oral bioavailability values estimated by the proposed model were more reasonable compared to those calculated by the model-independent AUC method. The proposed approach may be useful for estimating bioavailability of long half-life drugs when incomplete data points are available to characterize their elimination phase.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011977116543
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  • 93
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    Risedronate Gastrointestinal Absorption Is Independent of Site and Rate of Administration (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 228-232 
    Details
    ISSN: 1573-904X
    Keywords: risedronate ; gastrointestinal absorption ; gastrointestinal site ; bisphosphonate ; administration rate ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Two studies were conducted to compare the absorption of risedronate administered as a solution to three different gastrointestinal sites (study A) and to determine the extent of absorption of risedronate solution administered by rapid and slow infusion to the second part of the duodenum (study B). Methods. Each study was designed as a single-dose, crossover (three periods, study A; two periods, study B) trial in healthy male subjects, with a 14-day washout period between dosing. Subjects fasted overnight before drug administration and for 4 hours after drug administration. In study A, a risedronate solution of 40 mg in 30 mL of water was administered directly into the stomach, the second part of the duodenum, or the terminal ileum over 1 minute via a nasoenteral tube in a three-period crossover design. In study B, a risedronate solution of 40 mg in 30 mL of water was administered directly into the second part of the duodenum over 1 minute and over 1 hour in a randomized, two-period crossover design. Serum and urine samples were obtained for 48 hours after dosing for risedronate analysis. Results. Eight subjects completed each study. No statistically significant site-specific differences in any pharmacokinetic parameter were observed (study A). Based on the area under the serum concentration-time profile and the amount of drug excreted in the urine unchanged, the extent of risedronate absorption did not differ significantly following a rapid or a slow infusion (study B). Only minor symptomatic complaints were reported by subjects, such as headaches and body aches. Conclusions. These studies indicate that the rate and extent of risedronate absorption are independent of the site of administration along the gastrointestinal tract, and that the extent of absorption is not affected by the rate of administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011910517200
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  • 94
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    Use of the Stable Isotopes Technique to Evaluate the Bioavailability of a Pharmaceutical Form of Magnesium in Man (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 347-351 
    Details
    ISSN: 1573-904X
    Keywords: magnesium ; absolute bioavailability ; stable isotopes ; pharmacokinetics ; ICP-MS
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011947525377
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  • 95
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    Blood-Brain Barrier Equilibration of Codeine in Rats Studied with Microdialysis (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 570-575 
    Details
    ISSN: 1573-904X
    Keywords: microdialysis ; codeine ; morphine ; blood-brain barrier ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of the study was to investigate the distribution of codeine across the blood-brain barrier (BBB) in rats by micro-dialysis (MD). Methods. Rats were administered intravenous infusion of codeine in doses of (1) 10 mg/kg, (2) 20 mg/kg for 10 min, and (3) an exponential infusion for 2 h aiming at a plasma concentration of 2500 ng/ml, in a crossover design (n = 6). Microdialysis was used to determine codeine unbound concentrations in blood and brain extracellular fluid (ECF). Total brain tissue and plasma concentrations were also determined. Nalorphine was used as a calibrator for measurement of in vivo recovery. Results. Relative recovery and retrodialysis loss of codeine and nalorphine were similar both in vitro and in vivo. Codeine was rapidly transported into the brain ECF with identical influx and efflux clearance across the BBB. The AUC ratios of brain to blood were 0.99 ± 0.25 and 0.95 ± 0.16 for Dose 1 and 2, respectively. The Css ratio of brain to blood was 1.06 ± 0.12 for the exponential infusion. The half-lives were 25 ± 4 min, 22 ± 2 min in blood and 27 ± 5 min, 25 ± 5 min in brain for Dose 1 and Dose 2, respectively. Total brain tissue concentrations were 3.6 ± 1.2-fold higher than the unbound concentrations in brain. Codeine was demethylated to morphine with an unbound AUCbIood,morphine/AUCblood,codeine ratio of 7.7 ± 5.1% in blood. No morphine was detected in brain MD, but total concentrations were possible to measure. Conclusions. Codeine rapidly reached a distributional equilibrium with equal unbound concentrations in blood and brain. The brain transport of codeine did not show any dose-dependency.
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    URL: http://dx.doi.org/10.1023/A:1011929910782
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  • 96
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    Pulmonary Bioavailability of a Phosphorothioate Oligonucleotide (CGP 64128A): Comparison with Other Delivery Routes (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 583-591 
    Details
    ISSN: 1573-904X
    Keywords: administration ; antisense ; bioavailability ; gastrointestinal ; intra-peritoneal ; intra-tracheal ; ISIS 3521 ; oligonucleotide ; oral ; pharmacokinetics ; subcutaneous
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Phosphorothioate antisense oligodeoxynucleotides are promising therapeutic candidates. When given systemically in clinical trials they are administered via slow intravenous infusion to avoid their putative plasma concentration-dependent haemodynamic side-effects. In this study, we have evaluated alternative parenteral and non-parenteral administration routes which have the potential to enhance the therapeutic and commercial potential of these agents. Methods. The delivery of CGP 64128A by intravenous, subcutaneous, intra-peritoneal, oral and intra-tracheal (pulmonary) routes was investigated in rats using radiolabelled compound and supported by more specific capillary gel electrophoretic analyses. Results. Intravenously administered CGP 64128A exhibited the rapid blood clearance and distinctive tissue distribution which are typical for phosphorothioate oligodeoxynucleotides. Subcutaneous and intra-peritoneal administration resulted in significant bioavailabilities (30.9% and 28.1% over 360 min, respectively) and reduced peak plasma levels when compared with intravenous dosing. Administration via the gastrointestinal tract gave negligible bioavailability (〈2%). Intra-tracheal administration resulted in significant but dose-dependent bioavailabilities of 3.2, 16.5 and 39.8% at 0.06, 0.6 and 6.0 mg/kg, respectively. Conclusions. Significant bioavailabilities of CGP 64128A were achieved following subcutaneous, intra-peritoneal and intra-tracheal administration. Pulmonary delivery represents a promising mode of non-parenteral dosing for antisense oligonucleotides. The dose-dependent increase in pulmonary bioavailability suggests that low doses may be retained in the lungs for local effects whereas higher doses may be suitable for the treatment of a broader spectrum of systemic diseases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011934011690
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  • 97
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    Skin Mini-Erosion Sampling Technique: Feasibility Study with Regard to Serial Glucose Measurement (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 883-888 
    Details
    ISSN: 1573-904X
    Keywords: transdermal access ; skin erosion ; transdermal ; dermal interstitial fluid ; sampling ; glucose ; monitoring ; diabetes mellitus ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To describe a dermally non-invasive serial sampling technique and to test its clinical feasibility with regard to glucose measurement. Methods. A standardized skin mini-erosion devoid of the epidermal barrier, and covered by an artificial one, was formed by a suctioning technique. Interstitial fluid (IF) was extracted serially by brief application of negative pressure, and its glucose content compared with that in capillary or venous blood samples. Results. The procedure caused no discomfort. The epidermis regenerated rapidly after experimentation. There were no complications. In non-diabetic subjects (n = 13) the mean of all IF values measured daily for 6 days was 6.2 ± 0.1 mmol/1 (±SE). The corresponding capillary blood glucose value was 5.6 ± 0.1 mmol/1, and the venous glucose value was 5.4 ± 0.1 mmol/1. The differences between IF glucose values and invasive control values remained within narrow limits throughout. The 2SD limits of agreement for the differences were 1.44 mmol/1 (IF vs. capillary blood samples) and 1.76 mmol/1 (IF vs venous samples) respectively. The OGTT curves suggested glucose kinetics to be similar in IF and in capillary blood. In diabetic subjects, the mean of IF values determined serially during one day was 15.3 ± 1.0 mmol/1 (range, 6.7−21.8 mmol/1), and the corresponding mean capillary value was 12.0 ± 0.9 mmol/1 (range, 3.3−17.2 mmol/1). The ICC for all paired photometric observations was 0.948. Conclusions. The results suggest the new sampling technique to be a feasible approach for clinical and experimental purposes. A functionally integrated sampling patch is entering the clinical testing stage.
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    URL: http://dx.doi.org/10.1023/A:1011924631680
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    Pharmacokinetics and Biodistribution of a Nucleotide-Based Thrombin Inhibitor in Rats (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 904-910 
    Details
    ISSN: 1573-904X
    Keywords: GS522 ; oligodeoxynucleotide ; pharmacokinetics ; tritiated ; biodistribution ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To characterize the pharmacokinetic and tissue distribution profiles of a nucleotide-based thrombin inhibitor (GS522, phosphodiester oligonucleotide, GGTTGGTGTGGTTGG) following intravenous administration to rats. Methods. Pharmacokinetic study: 10 mg/kg, 20 mg/kg, 30 mg/kg (6 animals/dose) were administered to rats by rapid injection into the femoral vein. Blood samples were collected over a 45 minute period. Plasma concentrations of GS522 were determined using capillary gel electrophoresis with laser-induced fluorescence detection. Biodistribution Study: l0mg/kg (400μl, 31.46 μCi/ml) of 3H-GS522 was administered to rats by rapid injection into the femoral vein. The animals were sacrificed by decapitation at 1, 5, 10, 30, 60, 360 minutes post-dose (3 rats/point). Brain, blood, duodenum, eyes, heart, kidney, liver, lungs, muscle, pancreas, skin, spleen and vein samples were collected, processed and quantitated using liquid scintillation counting. Results. The pharmacokinetic profile declines in multiexponential manner, exhibiting extremely fast distribution and elimination (t1/2 = 7.6−9.0 min, Cl = 22.0−28.0 ml/min, V = 83.9−132.4 ml/kg). GS522 follows linear pharmacokinetics, with the area under the curve being proportional to the dose (Rsq = 0.9744). Highest radioactivity levels were detected in kidney, liver and blood (39.7, 15.7 and 15.3% dose/ respective organ). Less than 1% of the dose was detected in the heart, spleen and lungs, and 〉0.3% of the dose was found in the brain and eyes. The oligonucleotide associated radioactivity was uniformly distributed between the brain regions (left and right lobe and cerebellum). Six hours following the dose administration a statistically significant increase (p 〈 0.05) in radioactivity levels was observed in the brain, eyes, skin, liver, pancreas and vein. Conclusions. The pharmacokinetic and biodistribution profiles of GS522 following intravenous administration to rats at three doses were characterized. The oligonucleotide associated radioactivity was widely distributed in tissues. The amount of radioactivity sharply decreased with time in most tissues. Kidney, liver and muscle were the main sites of accumulation. The oligonucleotide associated radioactivity did not cross the blood brain barrier to an appreciable extent. In addition, a statistically significant increase (p 〈 0.05) in the radioactivity levels observed in select tissues suggested a re-uptake mechanism for intact oligonucleotide or its degradation products.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011980716659
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  • 99
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    Lack of In Vivo/In Vitro Correlations for 50 mg and 250 mg Primidone Tablets (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1085-1089 
    Details
    ISSN: 1573-904X
    Keywords: primidone ; bioavailability ; human ; pharmacokinetics ; in vitro dissolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To determine if large differences in the in vitro dissolution profiles for primidone tablets would result in significant bioavailability differences. Methods. Two separate bioavailability studies were conducted. The first study used 18 healthy subjects and compared the bioavailability of an old 50 mg tablet formulation, a new 50 mg tablet formulation, and a suspension containing 50 mg/ml of primidone. The second study enrolled 24 subjects who were to receive a new 250 mg tablet formulation, two lots of an old 250 mg tablet formulation and a 250 mg tablet from a second manufacturer. In vitro dissolution was conducted over 90 minutes, using USP 23 Apparatus 2 at 50 rpm, with 900 ml of water. Results. Dissolution at 90 minutes for the old and new 50 mg tablets was approximately 20% and 100%, respectively. The dissolution of the four 250 mg tablets ranged from approximately 30% to 100%. The 50 mg tablet that dissolved slower had a longer Tmax and a 14% lower Cmax than the more rapidly dissolving tablet, but the AUC(0−∞) values differed by only 3%. Only nine subjects completed the 250 mg study because of side effects. The differences in Cmax and AUC(0−∞) among the four 250 mg tablets were less than 7%. Conclusions. Even though there were large differences in the in vitro dissolution of the 50 mg and the 250 mg primidone tablets, the two 50 mg tablets were shown to be bioequivalent, as were the four 250 mg tablets.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011942530288
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  • 100
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    Guar Gum-Based Sustained Release Diltiazem (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1196-1201 
    Details
    ISSN: 1573-904X
    Keywords: guar gum ; sustained release ; extended release ; diltiazem ; dissolution ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study was performed to examine the use of guar gum to sustain the release of diltiazem under in vitro and in vivo conditions. Methods. Guar gum tablet formulations were prepared and evaluated under a variety of in vitro dissolution conditions. The formulations, along with Dilacor XR®, were administered to a group of eight fasted, healthy volunteers in a four period crossover study. Results. Varying the lot of guar gum as well as using guar from different suppliers had little effect on diltiazem dissolution. Also, dissolution of diltiazem from guar gum tablets was essentially independent of stir speed under normal conditions (USP Apparatus II). The stability of guar-based formulations under stressed conditions (40°C/75% relative humidity for 3 months) was also established. All four formulations gave similar plasma concentrations over time in the healthy volunteers pharmacokinetic study. Conclusions. Guar gum-based matrix tablets represent a simple and economical alternative to existing diltiazem sustained release dosage forms.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011931622536
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