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  • Articles  (273)
  • pharmacokinetics  (273)
  • Springer  (273)
  • 1995-1999  (273)
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  • Articles  (273)
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  • 1
    Electronic Resource
    Electronic Resource
    Effects of grapefruit juice ingestion – pharmacokinetics and haemodynamics of intravenously and orally administered felodipine in healthy men (1997)
    Springer
    European journal of clinical pharmacology 52 (1997), S. 139-145 
    Details
    ISSN: 1432-1041
    Keywords: Key words Felodipine ; Dietary interaction ; Flavonoids; pharmacodynamics ; pharmacokinetics ; grapefruit juice
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To examine the effect of grapefruit juice on the metabolism of felodipine following intravenous and oral administration. Methods: The study had a randomised, four-way, crossover design in 12 healthy males. Single doses of felodipine were given as an intravenous infusion for 1 h (1.5 mg) or as an oral extended release (ER) tablet (10 mg). Grapefruit juice (150 ml) or water was ingested 15 min prior to drug intake. Results: Intake of grapefruit juice did not significantly alter the intravenous pharmacokinetics of felodipine compared to control treatment, whereas after oral drug administration it did lead to an increase in the mean AUC and Cmax by 72% and 173%, respectively, and the mean absolute bioavailability was increased by 112%. The fraction of the oral felodipine dose reaching the portal system was increased from 45% to 80% when intake of drug was preceded by grapefruit juice ingestion. The pharmacokinetics of the primary metabolite, dehydrofelodipine, was affected by the intake of juice, resulting in a 46% increase in Cmax. Juice intake immediately before oral felodipine resulted in more pronounced haemodynamic effects of the drug as measured by diastolic blood pressure and heart rate. However, the haemodynamic effects of the intravenous administration were not altered by juice intake. Vascular-related adverse events were reported more frequently when oral drug administration was preceded by juice intake compared with control treatment. Taking grapefruit juice immediately prior to intravenous felodipine administration did not cause any alteration in the adverse event pattern. Conclusion: The main acute effect of the grapefruit juice on the plasma concentrations of felodipine is mediated by inhibition of gut wall metabolism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050263
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  • 2
    Electronic Resource
    Electronic Resource
    Pharmacokinetic interaction study of citalopram and cimetidine in healthy subjects (1997)
    Springer
    European journal of clinical pharmacology 52 (1997), S. 241-242 
    Details
    ISSN: 1432-1041
    Keywords: Key words Citalopram ; Cimetidine; drug ; drug interac‐tion ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050282
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  • 3
    Electronic Resource
    Electronic Resource
    Single-dose pharmacokinetics of paracetamol and its conjugates in Chinese non-insulin-dependent diabetic patients with renal impairment (1997)
    Springer
    European journal of clinical pharmacology 52 (1997), S. 285-288 
    Details
    ISSN: 1432-1041
    Keywords: Key words Paracetamol ; Renal failure; polar conjugates ; non-insulin-dependent diabetes mellitus (NIDDM) ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: A single oral dose of paracetamol (20 mg · kg−1) was given to 38 Chinese patients with non-insulin-dependent diabetes mellitus (NIDDM) who had either normal renal function or varying degrees of renal impairment, with creatinine clearances ranging from 4 to 123 ml · min−1 · 1.73 m−2. The plasma and urinary concentrations of paracetamol and its major metabolites were measured by high-performance liquid chromatography (HPLC). Results: The absorption and elimination of paracetamol were unaffected by renal impairment. However, the area under the plasma concentration time curve and the elimination half-life of paracetamol metabolites increased significantly with worsening renal insufficiency. Mean renal clearances of paracetamol and its conjugates were significantly reduced in these subjects. There was no evidence of altered metabolic activation with renal impairment. Conclusion: The results demonstrate that paracetamol disposition is minimally affected by diabetic nephropathy; however, extensive accumulation of conjugates may occur.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050291
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  • 4
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of nicardipine enantiomers in healthy young volunteers (1997)
    Springer
    European journal of clinical pharmacology 52 (1997), S. 289-292 
    Details
    ISSN: 1432-1041
    Keywords: Key words Nicardipine; enantiomers ; healthy volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objectives: The present study was conducted to compare pharmacokinetic behaviors of nicardipine enantiomers given in different doses with different formulations of racemic nicardipine in healthy volunteers. Methods: One or two 20-mg racemic nicardipine tablets, and a 40-mg sustained-release capsule of nicardipine were administered to eight healthy volunteers in a cross-over fashion and pharmacokinetic parameters were evaluated. Enantiomer concentrations were determined by GC-MS combined with chiral stationary phase HPLC. Results and conclusions: Serum concentration of (+)-nicardipine was approximately 2–3 times higher than that of (−)-nicardipine in 20- and 40-mg doses of conventional formulations and a non-linear increase in bioavailability with dose was demonstrated. The value for AUC of (+)-nicardipine was approximately 2.3–2.8 times greater than that of the (−)-nicardipine (P 〈 0.05) when 20 and 40 mg racemic nicardipine were administered in a conventional preparation. Relative bioavailability of the sustained-release preparation vs the conventional preparation was 28% and 44% for (+)- and (−)-nicardipine, respectively, for the 40-mg dose.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050292
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  • 5
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and bioavailability of oral and intramuscular artemether (1997)
    Springer
    European journal of clinical pharmacology 52 (1997), S. 307-310 
    Details
    ISSN: 1432-1041
    Keywords: Key words Artemether ; Thai males; malaria ; dihydroartemisinin ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The pharmacokinetics and bioavailability of artemether and dihydroartemisinin were investigated in eight Thai males following the administration of single oral and intramuscular doses of artemether (300 mg) in a randomized two-way cross-over study. Results: Both oral and intramuscular artemether were well-tolerated. In most cases, artemether and dihydroartemisinin were detected in plasma after 30 min and declined to levels below the limit of detection within 18–24 h. Compared with intramuscular administration, oral administration of artemether resulted in a relatively rapid but incomplete absorption [Cmax: 474 vs 540 ng · ml−1; t max: 2.0 vs 3.9 h; AUC: 2.17 vs 5.20 μg · h · ml−1]. Geographic means of lag-time and absorption half-life (t 1/2a) of oral vs intramuscular artemether were 0.28 and 1.1 h vs 0.30 and 2 h, respectively. t 1/2z was significantly shortened after the oral dose [2.8 vs 6.9 h]. Mean oral bioavailability relative to intramuscular administration was 43.2%. The ratio of the AUCs of artemether to dihydroartemisinin was significantly lower after the oral than after the intramuscular dose (geometric mean: 0.29 vs 0.60).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050295
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  • 6
    Electronic Resource
    Electronic Resource
    Transdermal nitroglycerin: clinical and pharmacokinetic consequences of renewing the patch and the application site (1997)
    Springer
    European journal of clinical pharmacology 52 (1997), S. 379-381 
    Details
    ISSN: 1432-1041
    Keywords: Key words Nitroglycerin; transdermal nitrate ; pharmacokinetics ; patch renewal ; exercise test
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: We examined whether nitroglycerin (glyceryl trinitrate, GTN) patch treatment for 24 h could induce local cutaneous changes that impaired drug delivery and clinical efficacy. Methods: Twenty angina patients were exercise-tested after 2 and 24 h of treatment and then 2 h after patch renewal. The patch was either renewed on a new skin location or on the previous application site in a randomised, double-blind, cross-over protocol. GTN plasma concentrations and finger plethysmography were obtained before and after each exercise test. Results and conclusions: The clinical efficacy, the effect seen on plethysmography and the GTN plasma concentrations tended to increase after patch renewal, regardless of the application site of the renewed patch. Hence, cutaneous changes of clinical importance could not be demonstrated.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050304
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  • 7
    Electronic Resource
    Electronic Resource
    Genetic polymorphism of CYP2C19 and lansoprazole pharmacokinetics in Japanese subjects (1997)
    Springer
    European journal of clinical pharmacology 52 (1997), S. 391-396 
    Details
    ISSN: 1432-1041
    Keywords: Key words Lansoprazole ; CYP2C19; genotype ; hydroxy lation ; polymorphism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: We investigated whether interindividual differences in the pharmacokinetic disposition of lansoprazole are attributed to the genetic polymorphism of CYP2C19 which occurred by two mutations, CYP2C19m1 and CYP2C19m2, in 20 Japanese subjects. Methods: Polymerase chain reaction (PCR) restriction fragment length polymorphism procedures were used to detect the CYP2C19m1 mutation in exon 5 and the CYP2C19m2 mutation in exon 4 using SmaI and BamHI, respectively. Results: Ten subjects were homozygous (wt/wt subjects) for the wt allele in both exon 5 and exon 4, four subjects were heterozygous (wt/m1) for the CYP2C19m1 mutation, and two subjects were heterozygous (wt/m2) for the CYP2C19m2. The remaining four subjects had both mutated alleles in CYP2C19 genes, i.e., two were homozygous (m1/m1) for the defect in exon 5 and two were heterozygous (m1/m2) for the two defects in exons 5 and 4. The subjects in group 1 (wt/wt, wt/m1 and wt/m2) were the extensive metabolizers (EMs) for 5-hydroxylation of lansoprazole and were in the range of hydroxylation indexes from 3.83 to 19.8, whereas the subjects in group 2 (m1/m1 and m1/m2) were the poor metabolizers (PMs) and the indexes were in the range of 38.5 to 47.6. In group 2, AUC, t1/2 and CL/f of lansoprazole were significantly greater, longer, and lower, respectively, than those in group 1. Conclusion: The hydroxylation of lansoprazole to 5-hydroxylansoprazole was apparently impaired in the subjects with the genetic defects of CYP2C19 (m1/m1 or m1/m2).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050307
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  • 8
    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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  • 9
    Electronic Resource
    Electronic Resource
    Design of a suitable formulation of FK613, a novel antiallergic agent, based on its pharmacokinetic and pharmacodynamic properties in healthy subjects (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 279-284 
    Details
    ISSN: 1432-1041
    Keywords: Antiallergic drug ; FK613 ; pharmacokinetics ; histamine skin-test ; drug formulation ; urinary excretion ; safety
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetic and pharmacodynamic properties of FK613, a novel indolyl piperidine derivative, were investigated after oral administrations of 5, 10 and 20 mg in hard gelatin capsules to healthy male volunteers. FK613 was rapidly and almost completely absorbed, and 〉89% was recovered in the urine as the unchanged form. The urinary excretion of FK613 was linearly correlated with plasma concentration and its low water solubility was the main concern regarding the safety. In another experiment using a double-blind crossover design, in which 0 (placebo), 5 and 20 mg FK613 were administered to determine the plasma concentration-effect relationship, suppression of the intradermal histamine-induced skin reaction by FK613 was observed. Thus, the maintenance of a plasma concentration of FK613 in the range of 80–250 ng · ml-1 was recommended to ensure the suppression of histamine-induced wheal by 〉50% and not to exceed the solubility in urine. To achieve this, a new hydrogel-type formulation of FK613 was developed, with the aim both of delaying its absorption, so as to suppress the sharp rise in plasma concentration, and of maintaining the effective concentration for a longer period of time. This formulation was administered after meals at the doses of 20, 30, 40, 50 and 60 mg, and at repeated doses of 40 mg twice daily for 6.5 days to evaluate the pharmacokinetics and safety in healthy subjects. The area under the plasma concentration curve increased linearly with dose, whereas maximum plasma concentration (Cmax) tended to peak as dose increased, indicating the desirable properties of this formulation. Although Cmax exceeded 250 ng/ml at doses of 30 mg or more, no urinary crystal formation was observed on careful inspection of urine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00226328
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  • 10
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of dexamethasone in premature neonates (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 477-483 
    Details
    ISSN: 1432-1041
    Keywords: Dexamethasone ; Premature neonates ; pharmacokinetics ; bronchopulmonary dysplasia ; infant ; newborn
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Dexamethasone is frequently used in premature neonates with bronchopulmonary dysplasia, however little is known about its disposition in this population. Methods: We evaluated the pharmacokinetics of dexamethasone in 9 premature neonates with a mean gestational age of 27.3 weeks and a postnatal age of 21.8 days. Results: There was a strong relationship between clearance (4.96 ml·min−1·kg−1) and gestational age (r=0.884). Pharmacokinetic parameters were grouped based on a gestational age of less than 27 weeks (Group I) and greater than 27 weeks (Group II). Mean clearance in group I and group II was 1.69 and 7.57 ml·min−1·kg−1, respectively. Mean distribution volume in group I and II was 1.26 and 2.19 l·kg−1, respectively. No significant relationships were noted between the disposition of dexamethasone and ventilator requirements or adverse effects. Conclusion: The pharmacokinetics of dexamethasone in premature neonates was related to gestational age.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00195934
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  • 11
    Electronic Resource
    Electronic Resource
    Therapeutic monitoring of nalbuphine: transplacental transfer and estimated pharmacokinetics in the neonate (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 485-489 
    Details
    ISSN: 1432-1041
    Keywords: Nalbuphine ; Neonate ; therapeutic drug monitoring ; placental transfer ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Nalbuphine, a mixed agonist-antagonist opiate, is commonly used as a systemic analgesic during labour. Recent reports of perinatal adverse effects prompted us to carry out therapeutic nalbuphine monitoring in obstetric analgesia. Because data on fetomaternal transfer are scarce and the pharmacokinetics of this drug in the neonate are largely unknown, we report data obtained from 28 parturients treated with nalbuphine either intramuscularly and/or intravenously during labour. Plasma nalbuphine levels were measured by high-performance liquid chromatography (HPLC) with electrochemical detection. At delivery, 30–150 min after maternal administration, nalbuphine concentrations ranged from 5.0 to 79.2 ng·ml−1 in mother plasma samples and from 3.0 to 46.6 ng·ml−1 in umbilical cord plasma samples. Nalbuphine concentrations were highly correlated to dose. The fetomaternal ratio was high: 0.74 and not correlated to the administered dose of nalbuphine. An estimated plasma half-life of 4.1 h was calculated from two determinations in the neonate based on the assumption of a monoexponential decay of nalbuphine concentrations. Apart from a flattening of the fetal heart rate tracing in 54% of the cases, only one neonate had a low Apgar score at birth. The apparent prolonged half-life of nalbuphine in the neonate indicates the usefulness of an intramuscular injection of naloxone to prevent recurrence of cardiorespiratory depression due to nalbuphine administration to the mother.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00195935
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  • 12
    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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  • 13
    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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  • 14
    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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  • 15
    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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  • 16
    Electronic Resource
    Electronic Resource
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00202173
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  • 17
    Electronic Resource
    Electronic Resource
    Paracetamol disposition in Thai patients during and after treatment of falciparum malaria (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 65-69 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00202175
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  • 18
    Electronic Resource
    Electronic Resource
    Multiple-dose clinical pharmacology of the catechol-O-methyl-transferase inhibitor tolcapone in elderly subjects (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 47-55 
    Details
    ISSN: 1432-1041
    Keywords: Key words Tolcapone ; Elderly; levodopa ; pharmacokinetics ; pharmacodynamics ; multiple-dose
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract. Objective: The purpose of this study was to assess the multiple-dose clinical pharmacology of tolcapone, a novel catechol-O-methyltransferase (COMT) inhibitor, in elderly subjects. Methods: The drug was administered orally t.i.d. for 7 days to four sequential groups of eight elderly subjects (gender ratio1:1) at doses of 100, 200, 400 and 800 mg in a double-blind, randomised, placebo-controlled, ascending-multiple-dose design. On days 2 and 7, a single dose of levodopa/benserazide 100/25 mg was given 1 h after the first intake of tolcapone. Plasma concentrations of tolcapone, its metabolite 3-O-methyltolcapone, levodopa and 3-O-methyldopa were determined during the course of the study in conjunction with COMT activity in erythrocytes. Results: Tolcapone was well tolerated at all dose levels, with a slight increase in gastrointestinal adverse events in females at higher doses. The drug was rapidly absorbed and eliminated and showed no changes in pharmacokinetics with time during multiple doses of 100 and 200 mg t.i.d. At doses of 400 and 800 mg t.i.d., tolcapone accumulated moderately as reflected in increased Cmax and AUC values. Despite the long half-life of 3-O-methyltolcapone (39 h), only minor accumulation occurred due to suppression of its formation by tolcapone. The pharmacodynamics of tolcapone did not change during the week of treatment as reflected in inhibition of COMT activity in erythrocytes, the derived parameters of the plasma concentration-effect relationship (inhibitory Emax model with constant EC50 values) and the effect on levodopa pharmacokinetics (1.6 to 2.5-fold increase in bioavailability). This suggests the absence of tolerance development and the insignificance of the altered pharmacokinetics at 400 and 800 mg t.i.d. with regard to the pharmacodynamics. Conclusion: The results of this study offer promising perspectives for the application of tolcapone as adjunct therapy to levodopa in the treatment of Parkinson’s disease.
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    URL: http://dx.doi.org/10.1007/s002280050068
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    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.
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    URL: http://dx.doi.org/10.1007/BF00198311
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    Electronic Resource
    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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  • 21
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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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    URL: http://dx.doi.org/10.1007/BF00194950
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    Effect of itraconazole on the pharmacokinetics and pharmacodynamics of zopiclone (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 331-334 
    Details
    ISSN: 1432-1041
    Keywords: Key words Zopiclone ; Itraconazole; drug interaction ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: We studied the possible interaction between itraconazole, a potent inhibitor of CYP3A, and zopiclone, a short-acting hypnotic. Methods: A double-blind, randomized, two-phase crossover design was used. Ten healthy young subjects received daily either 200 mg itraconazole or placebo for 4 days. On day 4 they ingested a single 7.5-mg oral dose of zopiclone. Plasma concentrations of zopiclone and itraconazole were determined and pharmacodynamic responses were measured up to 17 h. Results: Itraconazole significantly increased the Cmax of zopiclone from 49 to 63 ng ⋅ ml−1. The t1/2 of zopiclone was prolonged from 5.0 to 7.0 h. The AUC(0–∞) of zopiclone was increased from 415 to 719 ng ⋅ ml−1 h by itraconazole. No statistically significant differences were observed in the pharmacodynamic responses between the groups. Conclusion: Itraconazole has a statistically significant pharmacokinetic interaction with zopiclone but this is only of limited clinical importance, at least in young adults.
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    URL: http://dx.doi.org/10.1007/s002280050207
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  • 23
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    Effects of heat exposure in a Finnish sauna on the pharmacokinetics and metabolism of midazolam (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 335-338 
    Details
    ISSN: 1432-1041
    Keywords: Key words Midazolam ; Sauna; metabolism ; pharmacokinetics ; heat ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The effect of short-term heat exposure in a Finnish sauna on hepatic first-pass metabolism and the capacity to metabolize midazolam were studied in a crossover trial. Midazolam oral (15 mg) and intravenous (0.05 mg ⋅ kg−1) was given to 6 healthy young male volunteers, in random order, during a control session and a sauna bathing session (temperature 85–100° C, relative humidity 25–30%). Blood samples for the determination of plasma midazolam and α-hydroxy midazolam concentrations were taken for 6 h after drug administration. Results: After oral administration, the bioavailability and clearance of midazolam were not affected by sauna bathing, nor was there a significant difference in α-hydroxy midazolam plasma concentration or the α-hydroxy midazolam/midazolam AUC-ratio between the sessions. Midazolam Cmax was increased and its t1/2β was prolonged during the sauna session, but the clinical relevance of the findings appears to be modest. The pharmacokinetics of intravenous midazolam were not affected by sauna bathing. Conclusions: Short-term heat exposure may not affect the first-pass metabolism or hepatic capacity to metabolize midazolam.
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    URL: http://dx.doi.org/10.1007/s002280050208
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  • 24
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    Pharmacokinetic-pharmacodynamic modelling as a tool to evaluate the clinical relevance of a drug-food interaction for a nisoldipine controlled-release dosage form (1997)
    Springer
    European journal of clinical pharmacology 51 (1997), S. 473-480 
    Details
    ISSN: 1432-1041
    Keywords: Key words Nisoldipine ; Hypertension; Ca antagonist ; pharmacokinetics ; pharmacodynamics ; PK/PD modelling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Nisoldipine, a calcium antagonist of the dihydropyridine class, has been used in the treatment of hypertension and angina pectoris. A new controlled-release dosage form (nisoldipine coat-core, NCC) has been developed to allow once daily dosing. In addition to a formal food interaction study as requested by regulatory authorities for controlled-release dosage forms, a subsequent study was conducted to determine the clinical relevance of the changes in nisoldipine plasma concentration vs time profiles seen in the food effect study. Methods: After a placebo run-in phase of 6 days, 12 hypertensive patients started treatment with 20 mg NCC once daily (days 0–3, 5–6, 8–9). On days 4, 7 and 10 the NCC was substituted for 5, 10 and 20 mg nisoldipine solution, respectively, in order to obtain nisoldipine plasma concentration vs time profiles comparable to the ones resulting from the concomitant intake of food and NCC. Simultaneous measurements of blood pressure (BP) and nisoldipine concentration were performed on days 3, 4, 7 and 10. Results: The relationship between nisoldipine plasma concentrations and percentage reduction in BP [diastolic (DBP) and systolic (SBP), supine and standing] could be described by an Emax model. The mean maximum reduction (Emax) relative to baseline was about 36.4% and 37.7% (DBP, supine and standing) and 27.9% and 29.2% (SBP, supine and standing), respectively. The interindividual variability (% CV) in Emax was low, ranging from 17.6% to 28.8%. The mean nisoldipine plasma concentration corresponding to 50% of the maximum effect (EC50) ranged between 0.99 and 2.62 μg · l–1 with a pronounced interindividual variability (% CV) of 89.5–108.8%. Mean Cmax values after administration of the 30 and 40 mg NCC together with food were 4.5 and 7.5 μg · l–1, respectively. Based on the concentration-effect relationship established in the present study, the effect achieved with a concentration of 7.5 μg · l–1 will be about 77% of Emax for DBP and about 88% of Emax for SBP, respectively. Conclusion: At the time of maximum plasma concentration the additional decrease in BP relative to baseline due to the food effect will be about 7–15% for DBP and 3–9% for SBP. After administration of the 10␣mg solution with a mean Cmax of 8.7 μg · l–1, only headache and flush with mild severity have been reported as adverse events. These maximum concentrations are comparable to Cmax values seen after intake of 40 mg NCC with food. With regard to heart rate (HR) there were distinct differences between the two formulations: Following administration of 5, 10 and 20 mg nisoldipine solution, there were dose-dependent increases in HR by a maximum of 4, 12 and 16 beats · min−1, respectively, whereas the HR profile for the NCC was similar to that seen under placebo treatment.
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    URL: http://dx.doi.org/10.1007/s002280050233
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    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.
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    URL: http://dx.doi.org/10.1007/BF00192371
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    Electronic Resource
    Rectal pharmacokinetics of budesonide (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 293-298 
    Details
    ISSN: 1432-1041
    Keywords: Budesonide ; enema ; pharmacokinetics ; healthy subjects ; hepatic bypass
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics and systemic availability of budesonide after rectal administration of two single enema doses (2 mg in 100 ml fluid of almost identical composition) were compared in 15 healthy volunteers. In 11 of these subjects, 2 mg oral budesonide in a gelatine capsule was given on a separate occasion. An intravenous administration (0.5 mg) was given as reference. With this design, individual hepatic bypass of the rectally administered budesonide dose could be estimated. The pharmacokinetics of the two enema formulations were similar, although not bioequivalent. Mean systemic availability was 16% (range 4.2–43%) and 15% (3.2–50%) after rectal administration and 6.3% (2.4–10%) after oral administration. The rectal data revealed a small intra- but a substantial inter-subject variability in systemic availability. Cmax was 3.3 nmol·l-1 (0.95–8.2), 3.0 nmol·l-1 (0.64–8.9) and 1.3 nmol·l-1 (0.61–3.0), respectively, for the three formulations. Absorption was rapid and essentially terminated within 3 h after rectal dosing [tmax=1.3 h for both formulations (range 0.5–2.0)], but was slower after oral dosing [tmax=2.1 h (1.0–6.0)]. If a complete absorption after oral and rectal dosing is assumed, the fraction of the rectal dose entering the liver at first pass can be calculated to be 88% (55–99%). The higher systemic availability and intersubject variability after rectal dosing does not seem to be caused by differences in first-pass liver metabolism but rather by hepatic bypass of a varying portion of administered drug. This portion seems to be typical for an individual and might be explained by anatomical differences between subjects.
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    URL: http://dx.doi.org/10.1007/BF00226330
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    Electronic Resource
    Increase in magnesium plasma level after orally administered trimagnesium dicitrate (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 317-323 
    Details
    ISSN: 1432-1041
    Keywords: Magnesium ; Plasma level ; pharmacokinetics ; bioavailability ; circadian fluctuation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Magnesium plasma concentrations were measured in healthy probands before and after administration of trimagnesium dicitrate by the oral and intravenous routes. There was a notable circadian fluctuation of the plasma concentration with a peak in the evening hours. After oral administration of 12 and 24 mmol magnesium, a long-lasting, statistically significant increase in plasma magnesium concentration measured as the increase in area under the curve (AUC) between 0 and 12 h, of 3.1% and 4.6%, respectively, was found. After intravenous administration of 4 and 8 mmol magnesium, AUCs increased by 9.5% and 16.1%, respectively. The decline in the plasma magnesium concentration after i.v. administration was compatible with a three-compartment model with a terminal half-time of about 8 h. Although no absolute value of the oral bioavailability of trimagnesium dicitrate could be determined from the data, our results may be important in helping to elucidate the influence of magnesium preparations on the plasma magnesium concentration. By comparing the effects of different preparations, it should be possible to estimate the relative oral bioavailability and the bioequivalence of these preparations.
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    URL: http://dx.doi.org/10.1007/BF00226334
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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 
    Details
    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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    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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    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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    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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    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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    Pharmacokinetic interaction between cyclosporine and the dihydropyridine calcium antagonist felodipine (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 203-208 
    Details
    ISSN: 1432-1041
    Keywords: Key words Cyclosporine ; Felodipine; dehydrofelodi-pine ; pharmacokinetics ; blood pressure ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: In a double blind, randomised, placebo-controlled, cross-over study 12 healthy male volunteers were allocated to receive felodipine + placebo, cyclosporine + placebo, and felodipine + cyclosporine in order to investigate the interaction between the calcium channel blocker felodipine and cyclosporine as it affects the pharmacokinetics of felodipine, dehydrofelodipine, and cyclosporine, and 24-hour blood pressure measurements. Methods: Single doses of cyclosporine (capsules, 5 mg/kg body weight) and of felodipine (extended release (ER) tablets 10 mg) were given at a 1–2 week interval. Plasma drug concentrations were followed for 2 days after drug intake. Results: For cyclosporine, Cmax was increased after combined treatment (16%) compared to cyclosporine alone, but felodipine did not influence other kinetic parameters of cyclosporine. For felodipine, combined treatment with cyclosporine and felodipine increased AUC and Cmax (58% and 151%, respectively) and lowered mean residence time (24%) significantly compared to felodipine alone. For the metabolite dehydrofelodipine, too, AUC and Cmax were increased after the combined treatment (43% and 94%, respectively). Mean 24-hour systolic and diastolic blood pressures were significantly lower after felodipine, both when felodipine was given alone (121/68 mmHg) and in combination with cyclosporine (122/68 mmHg) compared to cyclosporine alone (127/73 mmHg). Conclusion: A combined single dose of cyclosporine and felodipine in healthy subjects increased the AUC and Cmax of felodipine suggesting a cyclosporine-induced decrease in the first-pass metabolism of felodipine, whereas the AUC of cyclosporine was only slightly increased by felodipine.
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    Effect of food on the bioavailability of oxybutynin from a controlled release tablet (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 221-223 
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    ISSN: 1432-1041
    Keywords: Key words Oxybutynin; effect of food ; N-desethyl oxybutynin ; bioavailability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The effect of food on the bioavailability of oxybutynin was assessed in a randomised cross-over study in 23 healthy volunteers. A single oral 10 mg dose of a controlled release oxybutynin tablet was administered after a high fat breakfast and to fasting subjects. The AUC, Cmax, tmax, t1/2 and MRT of oxybutynin and its active metabolite N-desethyloxybutynin were determined. Results: Breakfast did not change the AUC of oxybutynin but increased the AUC of N-desethyloxybutynin by about 20% . The Cmax of oxybutynin and N-desethyl oxybutynin were two-fold higher when the drug was administered after breakfast compared to the fasting state. Conclusion: Breakfast significantly reduced the MRT of oxybutynin and N-desethyloxybutynin.
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    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 
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    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.
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    Influence of age, frailty and liver function on the pharmacokinetics of brofaromine (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 387-391 
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    ISSN: 1432-1041
    Keywords: Liver function tests ; elderly ; pharmacokinetics ; geriatrics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The pharmacokinetics of brofaromine, a selective inhibitor of monoamine oxidase A, was evaluated in 12 frail elderly patients (66–92 y) and 12 healthy volunteers (20–35 y). Methods: Quantitative liver function tests were performed to show whether brofaromine elimination in the elderly could be predicted from noninvasive assessment of CYP1A2 activity (caffeine clearance) or liver plasma flow (sorbitol clearance). Results: In the elderly the AUC of brofaromine was significantly increased (e.g. for the 75 mg dose 43.2 vs 19.9 μmol*h·l−1, clearance was reduced (5.0 vs. 11.8 l·h−1), the volume of distribution was smaller (130 vs. 230 l), and the half-life was slightly increased (19.0 vs. 14.2 h). No significant correlation was observed between hepatic plasma flow and brofaromine clearance (r=0.41, P=0.05), whereas CYP1A2 activity and brofaromine clearance were tightly correlated (r=0.94, P〈0.0001). Conclusion: Caffeine clearance, a simple, noninvasive test of CYP1A2 activity, is predictive of brofaromine clearance.
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    Therapeutic monitoring of nalbuphine: transplacental transfer and estimated pharmacokinetics in the neonate (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 485-489 
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    ISSN: 1432-1041
    Keywords: Key words Nalbuphine ; Neonate; therapeutic drug monitoring ; placental transfer ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Nalbuphine, a mixed agonist-antagonist opiate, is commonly used as a systemic analgesic during labour. Recent reports of perinatal adverse effects prompted us to carry out therapeutic nalbuphine monitoring in obstetric analgesia. Because data on fetomaternal transfer are scarce and the pharmacokinetics of this drug in the neonate are largely unknown, we report data obtained from 28 parturients treated with nalbuphine either intramuscularly and/or intravenously during labour. Plasma nalbuphine levels were measured by high-performance liquid chromatography (HPLC) with electrochemical detection. At delivery, 30–150 min after maternal administration, nalbuphine concentrations ranged from 5.0 to 79.2 ng ⋅ ml−1 in mother plasma samples and from 3.0 to 46.6 ng ⋅ ml−1 in umbilical cord plasma samples. Nalbuphine concentrations were highly correlated to dose. The fetomaternal ratio was high: 0.74 and not correlated to the administered dose of nalbuphine. An estimated plasma half-life of 4.1 h was calculated from two determinations in the neonate based on the assumption of a monoexponential decay of nalbuphine concentrations. Apart from a flattening of the fetal heart rate tracing in 54% of the cases, only one neonate had a low Apgar score at birth. The apparent prolonged half-life of nalbuphine in the neonate indicates the usefulness of an intramuscular injection of naloxone to prevent recurrence of cardiorespiratory depression due to nalbuphine administration to the mother.
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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 
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    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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    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 
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    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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    Rectal pharmacokinetics of budesonide (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 293-298 
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    ISSN: 1432-1041
    Keywords: Key words Budesonide; enema ; pharmacokinetics ; healthy subjects ; hepatic bypass
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics and systemic availability of budesonide after rectal administration of two single enema doses (2 mg in 100 ml fluid of almost identical composition) were compared in 15 healthy volunteers. In 11 of these subjects, 2 mg oral budesonide in a gelatine capsule was given on a separate occasion. An intravenous administration (0.5 mg) was given as reference. With this design, individual hepatic bypass of the rectally administered budesonide dose could be estimated. The pharmacokinetics of the two enema formulations were similar, although not bioequivalent. Mean systemic availability was 16% (range 4.2–43%) and 15% (3.2–50%) after rectal administration and 6.3% (2.4–10%) after oral administration. The rectal data revealed a small intra- but a substantial inter-subject variability in systemic availability. Cmax was 3.3 nmol ⋅ l−1 (0.95–8.2), 3.0 nmol ⋅ l−1 (0.64–8.9) and 1.3 nmol ⋅ l−1 (0.61–3.0), respectively, for the three formulations. Absorption was rapid and essentially terminated within 3 h after rectal dosing [tmax = 1.3 h for both formulations (range 0.5–2.0)], but was slower after oral dosing [tmax = 2.1 h (1.0–6.0)]. If a complete absorption after oral and rectal dosing is assumed, the fraction of the rectal dose entering the liver at first pass can be calculated to be 88% (55–99%). The higher systemic availability and intersubject variability after rectal dosing does not seem to be caused by differences in first-pass liver metabolism but rather by hepatic bypass of a varying portion of administered drug. This portion seems to be typical for an individual and might be explained by anatomical differences between subjects.
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    Pharmacokinetics of quinine in patients with chronic renal failure (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 497-501 
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    ISSN: 1432-1041
    Keywords: Quinine ; Malaria ; pharmacokinetics ; chronic renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Methods: We investigated the pharmacokinetics of quinine (Qn) following administration of a single oral dose of 600 mg Qn sulphate in six male Thai patients with a moderate degree of chronic renal failure (CRF), and six male Thai subjects with normal renal function. Results: The drug was well tolerated in both groups of subjects; no major adverse reactions were observed. A marked alteration in the pharmacokinetics of Qn was found in patients with CRF compared to healthy subjects; there were six signifiicant changes in the pharmacokinetic parameters. Absorption was delayed, but increased in CRF (tmax 4.5 vs 1.6 h, Cmax 6.17 vs 3.45 μg·ml−1). Total clearance was significantly reduced 0.94 vs 2.84 ml·min−1·kg−1, whereas Vz/f remained unchanged (1.82 vs 2.78 1·kg−1). This resulted in the increased values of AUC and prolongation of the t1/2z and MRT in the patients (AUC 181.5 vs 61.8 μg·min−1·ml−1, t1/2z 26 vs 9.7 h, MRT 36.4 vs 11.3 h). Median concentrations of plasma unbound fraction of Qn collected at 4 h after drug administration in patients and healthy subjects were 7.3 vs 9.8%, respectively.
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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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    The effect of pH on the buccal and sublingual absorption of captopril (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 373-379 
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    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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    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 
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    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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    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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    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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  • 47
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    Haemodynamic effects and pharmacokinetics of oral d-and l-nebivolol in hypertensive patients (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 259-264 
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    ISSN: 1432-1041
    Keywords: Key words Nebivolol ; Hypertension; d ; l-enantiomers ; pharmacokinetics ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Nebivolol is a selective β1-adrenergic receptor blocker possessing an ancillary vasodilating effect. The objective of the present study was to study the haemodynamic and pharmacokinetic properties of nebivolol 5 mg once daily in a double-blind, placebo-controlled cross-over study. Methods: Fifteen patients, 12 men and 3 women, with essential hypertension were investigated. Blood pressure and peripheral circulation were determined after acute oral nebivolol administration, 5 mg daily, and after 4 weeks treatment. Results: The acute effect on blood pressure upon single-dosing was weak and non-significant. After 4 weeks both systolic blood pressure (152 vs 163 mmHg) and diastolic blood pressure (89 vs 97 mmHg) were significantly reduced after nebivolol treatment as compared to placebo. Following the first dose the venous volume was higher on placebo (5.88 ml ⋅ 100 ml−1 tissue) as compared to active nebivolol treatment (5.17 ml ⋅ 100 ml−1 tissue), while there were no statistically significant differences with regard to venous plethysmographic findings after 1 month on placebo (5.53 ml ⋅ 100 ml−1 tissue) or on active treatment (5.97 ml ⋅ 100 ml−1 tissue). Calculated peripheral resistance did not differ between active treatment (617 units) or placebo (548 units) after the first dose, whereas it was significantly lowered after 4 weeks of nebivolol treatment (483 units) as compared to placebo (593 units). Conclusions: Oral nebivolol 5 mg once daily lowered blood pressure and heart rate during steady state compared to placebo. Moreover, venous volume was reduced during acute but not steady-state dosing, while peripheral resistance was unaffected in the acute phase but reduced during steady state. Plasma concentrations of the separate enantiomers plus hydroxylated metabolites after the first and last dose in hypertensive patients were similar to those in healthy subjects.
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    Lack of pharmacodynamic and pharmacokinetic interaction between pantoprazole and phenprocoumon in man (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 277-281 
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    ISSN: 1432-1041
    Keywords: Key words Pantoprazole; Proton pump inhibitor drug interaction ; oral anticoagulant phenprocoumon ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Pantoprazole is a selective proton pump inhibitor characterized by a low potential to interact with the cytochrome P450 enzymes in man. Due to the clinical importance of an interaction with anticoagulants, this study was carried out to investigate the possible influence of pantoprazole on the pharmacodynamics and pharmacokinetics of phenprocoumon. Methods: Sixteen healthy male subjects were given individually adjusted doses of phenprocoumon to reduce prothrombin time ratio (Quick method) to about 30–40% of normal within the first 5–9 days and to maintain this level. The individual maintenance doses remained unaltered from day 9 on and were administered until day 15. Additionally, on study days 11–15, pantoprazole 40 mg was given per once daily. As a pharmacodynamic parameter, the prothrombin time ratio was determined on days 9 and 10 (reference value) and on days 14 and 15 (test value), and the ratio test/reference was evaluated according to equivalence criteria. Results: The equivalence ratio (test/reference) for prothrombin time ratio was 1.02 (90% confidence interval 0.95–1.09), thus fulfilling predetermined bioequivalence criteria (0.70–1.43). The pharmacokinetic characteristics AUC0–24h and Cmax of S(−)-and R(+)-phenprocoumon were also investigated using equivalence criteria. Equivalence ratios and confidence limits of AUC0–24h and of Cmax of S(−)-phenprocoumon (0.93, 0.87–1.00 for AUC0–24h; 0.95, 0.88–1.03 for Cmax) and of R(+)-phenprocoumon (0.89, 0.82–0.96; 0.9, 0.83–0.98) were within the accepted range of 0.8–1.25. Conclusion: Pantoprazole does not interact with the anticoagulant phenprocoumon on a pharmacodynamic or pharmacokinetic level. Concomitant treatment was well tolerated.
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    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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  • 50
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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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    Influence of food on the bioavailability and some pharmacokinetic parameters of diprafenone – a novel antiarrhythmic agent (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 315-319 
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    ISSN: 1432-1041
    Keywords: Key words Diprafenone; antiarrhythmics ; bioavailability ; human ; foods ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The present study was done to investigate the effect of food on the bioavailability of diprafenone. Methods: The most important pharmacokinetic parameters (Cmax, t1/2, AUC) and the relative oral availability of a solid oral preparation of racemic diprafenone were investigated when administered to fasting subjects and 10 min after a standard meal, in an open, randomised, crossover trial. Single oral doses of 100 mg were given on two different occasions, at least 1 week apart. The serum concentrations of diprafenone and its hydroxy-metabolite were determined up to 24 hours after administration by a sensitive, specific HPLC method. Fifteen healthy, male volunteers were enrolled in the trial. Their mean height, weight and age were 183 cm, 80 kg and 22 years, respectively. Fourteen volunteers were found to be rapid hydroxylators and one was a slow hydroxylator of debrisoquine. Only data from the rapid hydroxylators were used in the statistical analysis. Results: Food increased the oral bioavailability of diprafenone by approximately 50%. This effect was similar in rapid and in slow hydroxylators. The only slow hydroxylator in this trial had an AUC0–last ratio (with food/fasting) of 1.54. These findings suggest that diprafenone should be administered in a constant temporal relationship to food.
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    Absolute bioavailability of fluoride from disodium monofluorophosphate and enteric-coated sodium fluoride tablets (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 321-326 
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    ISSN: 1432-1041
    Keywords: Key words Sodium fluoride ; Disodium monofluorophosphate; absolute bioavailability ; pharmacokinetics ; elderly population
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objectives: The absolute bioavailability and other pharmacokinetic parameters of two fluoride formulations were investigated in 13 healthy volunteers, aged 61–70 years. Methods: The following formulations were administered, under fasting conditions, in a single-dose three-way cross-over design: tablets of 76 mg disodium monofluoro phosphate (MFP, equivalent to 10.0 mg F− ion), enteric-coated (e.c.) tablets of 25 mg sodium fluoride (NaFor, equivalent of 11.3 mg F− ion), and an isoosmotic aqueous injection solution (4 ml) of 22.1 mg sodium fluoride (NaFiv, equivalent of 10.0 mg F− ion). There was a wash-out period of at least one week between each administration. Blood was sampled before and during a 24-hour period after administration. For F− excretion urine was sampled 48 hours before (baseline) and over the 48 hours after the adminstration. Results: The mean t1/2 values of the three formulations were 8.3, 8.7 and 8.3 h for MFP, NaFor and NaFiv respectively, and were not significant different. Mean Cmax after MFP was significantly higher than after NaFor [344 vs 142 μg⋅l−1]. Mean tmax for MFP was shorter than for NaFor [1.1 vs 4.6 h]. MFP had significantly higher bioavailability [102.8%] than NaFor [64.2%]. Conclusion: The MFP formulation showed higher bioavailability with smaller variation than the NaFor formulation. MFP is preferable, therefore, for fluoride therapy in clinical practice, and changing from NaFor to MFP will require adjustment of the dose.
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    A single dose of ursodiol does not affect cyclosporine absorption in liver transplant patients (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 335-337 
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    ISSN: 1432-1041
    Keywords: Key words Cyclosporine ; Ursodiol; ursodeoxycholic acid ; absorption ; pharmacokinetics ; liver transplantation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To study the possible influence of ursodiol (ursodeoxycholic acid), a hydrophilic bile acid, on cyclosporine (CsA) bioavailability. Methods: Seven adult liver transplant recipients participated in a randomised cross-over pharmacokinetic study comparing ursodiol (600 mg) with placebo in single doses. Blood concentrations of CsA were measured by HPLC. Results: There was no significant effect of ursodiol on CsA absorption: AUC was 5011 vs 5486 ng⋅h⋅ml–1, Cmax was 832 vs 871 ng⋅ml–1 and tmax was 2 vs 2 h, after ursodiol and placebo, respectively. Conclusion: Although a significant period effect was observed, we conclude that a single dose of ursodiol has little effect on CsA absorption in liver transplant patients and that an interaction in the intestinal lumen between these two drugs is unlikely.
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    Limitations of the maximum entropy principle in devising drug input rate (1995)
    Springer
    European journal of clinical pharmacology 49 (1995), S. 139-143 
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    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.
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    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 
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    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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    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 
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    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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    Influence of age, frailty and liver function on the pharmacokinetics of brofaromine (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 387-391 
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    ISSN: 1432-1041
    Keywords: Key words Liver function tests; elderly ; pharmacokinetics ; geriatrics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The pharmacokinetics of brofaromine, a selective inhibitor of monoamine oxidase A, was evaluated in 12 frail elderly patients (66–92 y) and 12 healthy volunteers (20–35 y). Methods: Quantitative liver function tests were performed to show whether brofaromine elimination in the elderly could be predicted from noninvasive assessment of CYP1A2 activity (caffeine clearance) or liver plasma flow (sorbitol clearance). Results: In the elderly the AUC of brofaromine was significantly increased (e.g. for the 75 mg dose 43.2 vs 19.9 μmol*h⋅l−1, clearance was reduced (5.0 vs. 11.8 l⋅h−1), the volume of distribution was smaller (130 vs. 230 l), and the half-life was slightly increased (19.0 vs. 14.2 h). No significant correlation was observed between hepatic plasma flow and brofaromine clearance (r = 0.41, P = 0.05), whereas CYP1A2 activity and brofaromine clearance were tightly correlated (r = 0.94, P 〈 0.0001). Conclusion: Caffeine clearance, a simple, noninvasive test of CYP1A2 activity, is predictive of brofaromine clearance.
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    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 
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    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.
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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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    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.
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    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 
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    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.
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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 
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    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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    A comparison of the pharmacokinetics and pharmacodynamics of cilazapril between Chinese and Caucasian healthy, normotensive volunteers (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 57-62 
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    ISSN: 1432-1041
    Keywords: Key words Cilazapril ; Caucasians ; Chinese; cilazaprilat ; pharmacokinetics ; pharmacodynamics ; ACE inhibitor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract. Methods: The pharmacokinetics and pharmacodynamics of the angiotensin converting enzyme (ACE) inhibitor cilazapril were studied in 12 Chinese and 13 Caucasian, healthy, normotensive volunteers on their normal diet. Cilazapril was given orally as a single 2.5 mg capsule. Plasma was sampled for assay of the active metabolite, cilazaprilat, plasma renin activity (PRA), aldosterone, angiotensin I (AI) and ACE-activity. Plasma concentrations of the active drug were measured by radioimmunoassay. Blood pressure and heart rate were measured at regular intervals. Results: The pharmacokinetic parameters of cilazaprilat were similar in the two ethnic groups. No significant difference in plasma concentrations was found at any of the time points. However, the weight-adjusted plasma clearance was significantly higher in the Chinese group, which is compatible with their lower body weight. The effects on plasma hormones were also comparable, although there was a somewhat greater rise in PRA and greater fall in aldosterone levels in Chinese than in Caucasians. The effect of cilazapril on blood pressure and heart rate was greater than was previously reported in healthy volunteers. Systolic (SBP) and diastolic (DBP) blood pressure were significantly reduced in both groups, but there was a more prolonged reduction in DBP in Caucasians. In addition, heart rate (HR) was significantly increased from baseline from 5 h onwards in Chinese subjects and significantly higher in comparison with Caucasians at most time points from 1.5 h onwards. The pharmacokinetic parameters of cilazapril were essentially the same in healthy, normotensive Chinese and Caucasians. Cilazapril reduced blood pressure acutely in both groups, with good tolerance. The inhibition of ACE in relationship to time and the plasma concentrations of cilazaprilat were similar in the two groups, although the changes in PRA and aldosterone suggest an ethnic difference in the responses of the renin-angiotensin-aldosterone system.
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    Bioavailability of estradiol from a new matrix and a conventional reservoir-type transdermal therapeutic system (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 327-330 
    Details
    ISSN: 1432-1041
    Keywords: Key words Hormone replacement therapy; estradiol ; pharmacokinetics ; bioequivalence ; postmenopausal volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Bioavailability of estradiol delivered from a newly developed matrix-type transdermal therapeutic system (MTTS) was compared with that of the conventional reservoir-type system (RTTS). Both formulations have a nominal delivery rate of 50 μg per day of 17β-estradiol (E2). Plasma concentrations of E2 and estrone (E1) were determined at steady state during a 96-h application of each formulation to 34 postmenopausal volunteers, using a two-stage randomized two-period crossover design. Results: The MTTS proved to be equivalent to the RTTS with respect to the extent of E2 absorption. Due to differences in patch design and composition, the rate of absorption was different between the two systems, with less fluctuating E2 plasma levels during application of the matrix system. Local tolerability and adhesion of MTTS appeared to be better than those of the reservoir system.
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    Cardiovascular effects of different infusion rates of sufentanil in patients undergoing coronary surgery (1997)
    Springer
    European journal of clinical pharmacology 51 (1997), S. 359-366 
    Details
    ISSN: 1432-1041
    Keywords: Key words Sufentanil ; pharmacokinetics ; haemo dynamics ; different infusion rates ; coronary surgery
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract    Objective: Pharmacokinetics and haemodynamic effects of a total dose of 15 μg · kg−1 sufentanil, an opioid anaesthetic agent, were studied in patients undergoing aortocoronary bypass surgery at three infusion rates of 30 (group I), 5 (group II), and 2 (group III) μg · kg−1 · min−1, respectively. Results: Plasma concentrations of sufentanil could be optimally characterized by a linear biexponential pharmacokinetic model. Non-compartmental analyses indicated that there was no significant difference in the values of clearance (11.6, 13.3, 14.3 ml · min−1 · kg−1), steady-state volume of distribution (0.220, 0.255 and 0.331 l · kg−1) and mean residence time (18.8, 13.3 and 14.3 min) among the groups. The observed mean Cmax values of 421 (group I), 125 (group II), and 53 (group III) ng · ml−1 and observed mean AUC values from 0 to 3 min were all consistent with the dosing regimens. There were large inter-individual variations in haemodynamic response. Compared to plasma data, a delay in haemodynamic effects was found. Times to reach peak haemodynamic effect ranged from 4.3 to 4.9 min for group I, from 4.6 to 6.1 min for group II, and from 9.9 to 11.3 for group III. Except heart rate, peak haemodynamic effects in these study patients generally ranged from 20.9% to 35.2%. Significant reductions in the area under the effect-time profiles of mean arterial blood pressure and systemic vascular resistance were observed in group II and group III, but not in group I. Significant reductions in the area under the effect-time profiles of left ventricular stroke work index were observed in group III only. No effect on heart rate was found in any group. Conclusion: Our findings suggested that a slower infusion rate of sufentanil at a dose of 15 μg · kg−1 tends to give a greater reduction in mean arterial blood pressure, systemic vascular resistance, and left ventricular stroke work index than does a faster infusion rate.
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    Effect of route of administration of fluconazole on the interaction between fluconazole and midazolam (1997)
    Springer
    European journal of clinical pharmacology 51 (1997), S. 415-419 
    Details
    ISSN: 1432-1041
    Keywords: Key words Midazolam ; Fluconazole ; CYP3A4 ; interaction ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Midazolam is a short-acting benzodiazepine hypnotic extensively metabolized by CYP3A4 enzyme. Orally ingested azole antimycotics, including fluconazole, interfere with the metabolism of oral midazolam during its absorption and elimination phases. We compared the effect of oral and intravenous fluconazole on the pharmacokinetics and pharmacodynamics of orally ingested midazolam. Methods: A double-dummy, randomized, cross-over study in three phases was performed in 9 healthy volunteers. The subjects were given orally fluconazole 400 mg and intravenously saline within 60 min; orally placebo and intravenously fluconazole 400 mg; and orally placebo and intravenously saline. An oral dose of 7.5 mg midazolam was ingested 60 min after oral intake of fluconazole/placebo, i.e. at the end of the corresponding infusion. Plasma concentrations of midazolam, α-hydroxymidazolam and fluconazole were determined and pharmacodynamic effects were measured up to 17 h. Results: Both oral and intravenous fluconazole significantly increased the area under the midazolam plasma concentration-time curve (AUC0–3, AUC0–17) 2- to 3-fold, the elimination half-life of midazolam 2.5-fold and its peak concentration (Cmax) 2- to 2.5-fold compared with placebo. The AUC0–3 and the Cmax of midazolam were significantly higher after oral than after intravenous administration of fluconazole. Both oral and intravenous fluconazole increased the pharmacodynamic effects of midazolam but no differences were detected between the fluconazole phases. Conclusion: We conclude that the metabolism of orally␣administered midazolam was more strongly inhibited by oral than by intravenous administration of fluconazole.
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    URL: http://dx.doi.org/10.1007/s002280050223
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    Lack of interaction between meloxicam and warfarin in healthy volunteers (1997)
    Springer
    European journal of clinical pharmacology 51 (1997), S. 421-425 
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    ISSN: 1432-1041
    Keywords: Key words Warfarin ; Meloxicam ; interaction ; pharmacokinetics ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The effect of multiple oral doses of meloxicam 15 mg on the pharmacodynamics and pharmacokinetics of warfarin was investigated in healthy male volunteers. Warfarin was administered in an individualized dose to achieve a stable reduction in prothrombin times calculated as International Normalized Ratio (INR) values. Then INR- and a drug concentration-time profile was determined. For the interaction phase, meloxicam was added for 7 days and then INR measurements and the warfarin drug profiles were repeated for comparison. Overall, warfarin treatment lasted for 30 days. Results: Warfarin and meloxicam were well tolerated by healthy volunteers in this study. Thirteen healthy volunteers with stable INR values entered the interaction phase. Prothrombin times, expressed as mean INR values, were not significantly altered by concomitant meloxicam treatment, being 1.20 for warfarin alone and 1.27 for warfarin with meloxicam cotreatment. R- and S-warfarin pharmacokinetics were similar for both treatments. Geometric mean (% gCV) AUCSS values for the more potent S-enantiomer were 5.07 mg · h · l−1 (27.5%) for warfarin alone and 5.64 mg · h · l−1 (28.1%) during the interaction phase. Respective AUCSS values for R-warfarin were 7.31 mg · h · l−1 (43.8%) and 7.58 mg · h · l−1 (39.1%). Conclusion: The concomitant administration of the new non-steroidal anti-inflammatory drug (NSAID) meloxicam affected neither the pharmacodynamics nor the pharmacokinetics of a titrated warfarin dose. A combination of both drugs should nevertheless be avoided and, if necessary, INR monitoring is considered mandatory.
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    URL: http://dx.doi.org/10.1007/s002280050224
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    Stereoselective pharmacokinetics of mefloquine in young children (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 241-244 
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    ISSN: 1432-1041
    Keywords: Key words Mefloquine ; Children; enantiomer ; pharmacokinetics ; stereoselectivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: the stereospecificity of mefloquine pharmacokinetics in children has been investigated. Patients: Twelve children aged 6 to 24 months were treated for uncomplicated falciparum malaria with a single oral dose of 25 mg⋅kg−1 racemic mefloquine in combination with sulfadoxine and pyrimethamine. Methods: concentrations of mefloquine enantiomers were determined using a coupled achiral-chiral chromatographic system. Pharmacokinetic parameters were calculated using model-independent analysis. Results: Maximum plasma concentrations, areas under the curve and apparent plasma elimination half-lives were higher for the (−) enantiomer than its antipode. In contrast, the apparent volume of distribution (V/f) and total clearance (Cl/f) values were higher for the (+) enantiomer. Conclusion: the stereoselectivity of mefloquine pharmacokinetics is similar to that observed in adults.
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    Pharmacokinetics of moxisylyte in healthy volunteers after intracavernous injection of increasing doses (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 411-415 
    Details
    ISSN: 1432-1041
    Keywords: Moxisylyte ; pharmacokinetics ; intracavernous administration ; healthy volunteers ; adverse events ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The concentration-time profiles of specific metabolites of moxisylyte, an α-adrenoceptor blocking agent, in the plasma and urine from 18 healthy volunteers were investigated after intracavernous (IC) administrations at three dose levels (10, 20 and 30 mg). Results: Four metabolites, unconjugated desacetyl-moxisylyte (DAM), DAM glucuronide, and DAM and monodesmethylated DAM (MDAM) sulphates were found in plasma and urine. For all metabolites, t1/2 elimination was independent of the administered dose (1.19 h for unconjugated DAM; 1.51 h for DAM glucuronide; 1.51 h for DAM sulphate; and 2.17 h for MDAM sulphate). Cmax and AUC increased in direct proportion to dose, except for the inactive DAM glucuronide. Any the differences detected were small and equivalence of the three doses can be accepted. Conclusion: The pharmacokinetics of moxisylyte in humans following intracavernous administration were linear in the dose range 10 to 30 mg.
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    Determination of plasma concentration of the cardioprotective preparation histochrome (1996)
    Springer
    Bulletin of experimental biology and medicine 122 (1996), S. 1222-1224 
    Details
    ISSN: 1573-8221
    Keywords: free-radical pathology ; antioxidants ; polyhydroxynaphthoquinones ; histochrome ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract A method for measuring the plasma concentration of histochrome is described. Echinochrome, a naturally occurring polyhydroxynaphthoquinone with antioxidant and cardioprotective activities, is the active ingredient of histochrome. Plasma histochrome concentration is measured in patients with acute myocardial infarction. This method can be used for pharmacokinetic analysis.
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    Pharmacokinetics of prednisolone and its impact on cortisol kinetics in the blood serum of apparently healthy human subjects (1996)
    Springer
    Bulletin of experimental biology and medicine 122 (1996), S. 695-697 
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    ISSN: 1573-8221
    Keywords: prednisolone ; cortisol ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Individual characteristics of prednisolone and cortisol pharmacokinetics in five young healthy subjects administered prednisolone in a single oral dose of 25 mg are described. The results suggests that prednisolone inhibits the glucocorticoid function of the adrenal cortex. It is concluded that the pharmacokinetics of prednisolone can be assessed from the reductions in serum cortisol concentration which it causes.
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    Pharmacokinetics of antipyrine in rats with different resistance to hypoxia in cold stress (1998)
    Springer
    Bulletin of experimental biology and medicine 126 (1998), S. 1098-1099 
    Details
    ISSN: 1573-8221
    Keywords: pharmacokinetics ; antipyrine ; individual resistance to hypoxia ; cold stress
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract It is shown that the parameters of antipyrine pharmacokinetics during cold exposure depend on individual resistance to hypoxia. High-resistant rats are characterized by less intense metabolism and more rapid normalization of pharmacokinetic parameters than lowresistant rats characterized by shortened elimination half-time corresponding to a more rapid metabolism of xenobiotics under conditions of cold stress.
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    Assuming Peripheral Elimination: Its Impact on the Estimation of Pharmacokinetic Parameters of Muscle Relaxants (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 491-512 
    Details
    ISSN: 1573-8744
    Keywords: muscle relaxants ; peripheral elimination ; pharmacokinetics ; peripheral concentrations ; volume of distribution ; pharmacokinetic model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract For anesthetic drugs undergoing nonorgan-based elimination, there is a definite trend towards using pharmacokinetic (PK) models in which elimination can occur from both central (k10 ) and peripheral compartments(k20 ). As the latter cannot be assessed directly, assumptions have to be made regarding its value. The primary purpose of this paper is to evaluate the impact of assuming various degrees of peripheral elimination on the estimation of PK parameters. For doing so, an explanatory model is presented where previously published data from our laboratory on three muscle relaxants, i.e., atracurium, doxacurium, and mivacurium, are used for simulations. The mathematical aspects for this explanatory model as well as for two specific applications are detailed. Our simulations show that muscle relaxants having a short elimination half-life are more affected by the presence of peripheral elimination as their distribution phase occupies the major proportion of their total area under the curve. Changes in the exit site dependent PK parameters (Vdss ) are also mostly significant when k20 is smaller than k10 . Although the physiological processes that determine drug distribution and those affecting peripheral elimination are independent, the two are mathematically tied together in the two-compartment model with both central and peripheral elimination. It follows that, as greater importance is given to k20 , the rate of transfer from the central compartment (k12 ) increases. However, as a result of a proportional increase in the volume of the peripheral compartment, peripheral concentrations remain unchanged whether or not peripheral elimination is assumed. These findings point out the limitations of compartmental analysis when peripheral elimination cannot be measured directly.
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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 
    Details
    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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    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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    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 Methylprednisolone in Rats: Dose-Proportionality and Chronic-Dose Pharmacokinetics/Pharmacodynamics (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 141-145 
    Details
    ISSN: 1573-904X
    Keywords: liposomes ; methylprednisolone ; pharmacokinetics ; dose dependence ; multiple doses ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Methylprednisolone (MPL) encapsulated in liposomes (L-MPL) targets the immune system and enhances immunosuppressive activity of the steroid. We performed dose-dependent and chronic dose studies of L-MPL versus MPL. Methods. Male Lewis rats received 10 mg/kg IV bolus doses of L-MPL (Solu-Medrol). Plasma samples were obtained over an 8 day period and MPL concentrations were assayed by HPLC. Immunosuppressive effects were measured as inhibition of ex vivo splenocyte proliferation induced with PHA. Results. Drug concentrations declined in a similar manner over the first few hours following MPL or L-MPL. Free MPL was cleared from plasma by 6 hr, while the same dose of L-MPL resulted in persistance over an 8-day period. Dose-dependent changes in pharmacokinetic parameters were observed for both free and liposomal drug. Increasing the dose from 2 to 10 mg/kg led to increased clearance from 5.9 to 10.5 (MPL) and from 1.8 to 2.3 L/hr/kg (L-MPL). Blastogenesis was suppressed over 5 days with return to the baseline at day 8 (L-MPL); free MPL produced immunosuppression only over 10 hr. Multiple 2 mg/kg IV doses of L-MPL versus MPL twice a week produce plasma drug profiles similar to those obtained after single doses, indicating that neither free nor liposomal steroid accumulates in tissues. Liposomes without drug simultaneously administered with MPL caused partial prolongation of plasma steroid half-life (8.4 hr). Conclusions. These studies clarify factors causing prolonged drug persistence and immunosuppression with L-MPL. Nonlinear disposition, irregular pharmacokinetics, and secondary effects of the liposomes are complicating factors in use of L-MPL.
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    Percutaneous Absorption of Ketoprofen from Different Anatomical Sites in Man (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 168-172 
    Details
    ISSN: 1573-904X
    Keywords: ketoprofen ; nonsteroidal anti-inflammatory agent ; topical application ; percutaneous absorption ; regional variation ; pharmacokinetics ; urinary excretion ; enantiomers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of this study was to investigate the percutaneous absorption of ketoprofen applied topically to different anatomical sites on the body. Methods. The study design was a randomized, four-way crossover in 24 healthy male subjects. One gram of ketoprofen 3% gel (30 mg dose) was applied every six hours for 25 doses over a 100 cm2 of the back, arm, and knee. A 0.5 ml of ketoprofen solution (60 mg/ml) was applied to the back as a reference treatment. Plasma and urine samples were obtained for the assay of racemic ketoprofen and ketoprofen enantiomers (S and R), respectively. Results. The relative bioavailabilities of ketoprofen gel were 0.90 ± 0.50, 1.08 ± 0.63, and 0.74 ± 0.38 when applied to the back, arm, and knee, respectively. The plasma ketoprofen Cmax for gel applied to the back and arm were similar (p 〉 0.05) but Cmax was lower when applied to the knee (p 〈 0.05). The time to Cmax ranged from 2.7 to 4.0 hours and was similar for gel treatments on the back and arm, but longer for the knee treatment. The fraction of dose excreted in urine as total S and R enantiomers ranged from 5.41 to 9.10%. Conclusions. The percutaneous absorption of ketoprofen was similar when applied to either the back or arm but was lower when applied to the knee.
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    Design of Biological Equivalence Programs for Therapeutic Biotechnology Products in Clinical Development: A Perspective (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1427-1437 
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    ISSN: 1573-904X
    Keywords: bioequivalence ; biotechnology products ; recombinant proteins ; pharmacokinetics ; pharmacodynamics ; efficacy ; immunogenicity ; safety
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The determination of biological equivalence requires that studies are conducted to establish that two molecules, two formulations, or two dosing regimens, for example, are indistinguishable with respect to safety and efficacy profiles that have been previously established. The criteria that are used to establish biological equivalence will depend on the nature of the change (e.g., molecular, process, formulation), the stage of the development program, the duration of treatment, and the intended clinical indications. Key components of an equivalence program include chemical characterization, in vitro and in vivo bioactivity against reference material, pharmacokinetics, and safety. Special considerations for patient populations, endogenous concentrations, environmental factors, immunogenicity, assay methodology, biochemical identity, pharmacodynamic equivalence, and statistical methodology are discussed. In addition, the role of preclinical in vivo assessments is addressed. Specific case studies provide insight into the varied nature of approaches that are currently employed.
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    Uptake Is the Rate-limiting Step in the Overall Hepatic Elimination of Pravastatin at Steady-state in Rats (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1559-1564 
    Details
    ISSN: 1573-904X
    Keywords: carrier-mediated active transport ; well-stirred model ; parallel-tube model ; dispersion model ; nonlinearity ; pharmacokinetics ; tissue-distribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Of the HMG-CoA reductase inhibitors, the hydrophilic pravastatin has been shown to exhibit relatively specific inhibition of cholesterol synthesis in the liver. As one of the reasons for this relatively specific pharmacological activity, we demonstrated that the tissue distribution of pravastatin is limited because of its high hydrophilicity, while hepatic uptake by active transport takes place at the liver surface via a multispecific anion transporter (M. Yamazaki et al., Am. J. Physiol., 264, G36-44, 1993). In this study, we examined the hepatic elimination of pravastatin at steady-state. Methods. After i.v. infusion, the plasma concentrations of pravastatin in both arterial and hepatic venous blood were measured. Results. The hepatic availability at steady-state exhibited a clear increase on increasing the infusion rate of pravastatin. The total hepatic elimination rate at steady-state exhibited Michaelis-Menten type saturation with the drug concentration in the capillary defined by typical mathematical models (i.e., well-stirred, parallel-tube and dispersion models), Km and Vmax values being comparable with those obtained from analysis of the initial uptake velocity using in vitro isolated hepatocytes. Conclusions. These results indicate that overall hepatic intrinsic clearance of pravastatin at steady-state is regulated by the uptake process, followed by rapid metabolism and/or biliary excretion with minimal efflux to the circulating blood.
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    Evaluation of Pharmacokinetic Studies: Is It Useful to Take into Account Concentrations Below the Limit of Quantification? (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 839-845 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; precision ; accuracy ; limit of quantification
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Based on real data, to evaluate the usefulness of taking into account samples with values below the limit of quantification (LOQ) for the evaluation of pharmacokinetic studies. Methods. To compare for two drugs, after single dose administration the pharmacokinetic parameters obtained by using a poorly sensitive assay (PSA) and a highly sensitive assay (HSA), acting as reference; To evaluate the results of pharmacokinetic studies in the light of different values for the LOQ. Results. Under certain conditions, such as homogeneous population, sufficient subject number, sufficient sampling times and acceptable accuracy (CV 〈 20%) for the concentrations, it is possible to get valuable and more reliable kinetic information by using concentrations obtained with a poor precision (CV 〉 20%). This is especially true for the parameters associated with the terminal phase, such as t1/2β and AUC, but also for parameters depending to a lesser extent on the terminal phase, such as tl/2α and AUCtn. Moreover, the mean concentration time curve is by far best defined by using all the concentrations. Conclusions. In some situations, it is preferable to use concentrations with values below the LOQ to evaluate the results of pharmacokinetic studies. However, this should not be the rule, especially when this does not bring any additional information, or when it is possible to increase the sensitivity of the bioanalytical assay.
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    Bioequivalence of a Highly Variable Drug: An Experience with Nadolol (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1109-1115 
    Details
    ISSN: 1573-904X
    Keywords: nadolol ; pharmacokinetics ; bioequivalence ; variability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To assess the bioequivalence of nadolol 40mg and 160mg tablets (Zenith-Goldline Pharmaceuticals) using Corgard® 40mg and 160mg tablets (Bristol-Meyers Squibb) as reference products, to estimate the effect of food in the gastrointestinal tract on nadolol bioavailability, and to evaluate the effectiveness of standard pharmacokinetic metrics AUCt, AUC∞, and Cmax in bioequivalence determinations. Methods. Four bioequivalence studies were conducted as described in the FDA Guidance. Four additional studies of varying designs were conducted to establish bioequivalence of the 40mg tablet in terms of Cmax. Results. Fasted and food-effect studies of the 160mg tablet clearly established bioequivalence and revealed an unexpected reduction in nadolol bioavailability from test and reference products in the presence of food. The food-effect study of the 40mg tablet (80mg dose) revealed a similar reduction in bioavailability from each product. Fasted studies of the 40mg tablet (80mg dose) established bioequivalence in terms of AUCt and AUC∞. However, Cmax criteria proved extremely difficult to meet in the initial 40mg fasted study because of the large variability, leading to additional studies and ultimately requiring an unreasonable number of subjects. Conclusions. Final results clearly established bioequivalence of both strengths and characterized an unexpected food effect which did not appear to be formulation-related. However, the Cmax of nadolol is only slightly sensitive to absorption rate and the relatively large variability of Cmax reduces its effectiveness as a bioequivalence metric. Findings suggest that bioequivalence criteria for highly variable drugs should be reconsidered.
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    Characterization of AUCs from Sparsely Sampled Populations in Toxicology Studies (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1283-1290 
    Details
    ISSN: 1573-904X
    Keywords: toxicokinetics ; sparse sampling ; pharmacokinetics ; toxicology
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The objective of this work was to develop and validate blood sampling schemes for accurate AUC determination from a few samples (sparse sampling). This will enable AUC determination directly in toxicology studies, without the need to utilize a large number of animals. Methods. Sparse sampling schemes were developed using plasma concentration-time (Cp-t) data in rats from toxicokinetic (TK) studies with the antiepileptic felbamate (F) and the antihistamine loratadine (L); Cp-t data at 13–16 time-points (N = 4 or 5 rats/time-point) were available for F, L and its active circulating metabolite descarboethoxyloratadine (DCL). AUCs were determined using the full profile and from 5 investigator designated time-points termed “critical” time-points. Using the bootstrap (re-sampling) technique, 1000 AUCs were computed by sampling (N = 2 rats/point, with replacement) from the 4 or 5 rats at each “critical” point. The data were subsequently modeled using PCNONLIN, and the parameters (ka, ke, and Vd) were perturbed by different degrees to simulate pharmacokinetic (PK) changes that may occur during a toxicology study due to enzyme induction/inhibition, etc. Finally, Monte Carlo simulations were performed with random noise (10 to 40%) applied to Cp-t and/or PK parameters to examine its impact on AUCs from sparse sampling. Results. The 5 time-points with 2 rats/point accurately and precisely estimated the AUC for F, L and DCL; the deviation from the full profile was ~10%, with a precision (%CV) of ~15%. Further, altered kinetics and random noise had minimal impact on AUCs from sparse sampling. Conclusions. Sparse sampling can accurately estimate AUCs and can be implemented in rodent toxicology studies to significantly reduce the number of animals for TK evaluations. The same principle is applicable to sparse sampling designs in other species used in safety assessments.
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    Distribution Kinetics of Diazepam, Lidocaine and Antipyrine in the Isolated Perfused Rat Hindlimb (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 1640-1643 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; indicator dilution ; permeability ; dispersion ; model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1012198922671
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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 
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    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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    Effect of Norfloxacin on Theophylline Disposition: A Comparison with Other Fluoroquinolones (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 257-262 
    Details
    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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    URL: http://dx.doi.org/10.1023/A:1016287128048
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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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    Cyclodextrins: Their Future in Drug Formulation and Delivery (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 556-567 
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    ISSN: 1573-904X
    Keywords: cyclodextrins ; drug formulation ; drug delivery ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Since their discovery, cyclodextrins and their ability to form inclusion complexes have fascinated chemists, formulators and recently, entrepreneurs. This mini-review has as its objective, a critical assessment of the current status of cyclodextrins in the formulation and delivery of pharmaceuticals and commentary on their potential future uses. The emphasis will be on answers to common questions often asked of pharmaceutical scientists working in this area. Why use cyclodextrins for drug solubilization and stabilization when alternative techniques are available? Why the greater interest in modified cyclodextrins and not the parent cyclodextrins? If a drug forms a strong cyclodextrin inclusion complex, how is the drug releasedin vivo? Does the injection of a cyclodextrin/drug complex alter the pharmacokinetics of the drug? Are there drug products on the market which contain cyclodextrins? What is the regulatory status of cyclodextrins? Although definitive answers to all these questions are not possible at this time, many of these questions are answerable, and educated and informed responses are possible for the rest.
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    URL: http://dx.doi.org/10.1023/A:1012136608249
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    Sumatriptan Absorption from Different Regions of the Human Gastrointestinal Tract (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 138-143 
    Details
    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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    The Disposition of Valproyl Glycinamide and Valproyl Glycine in Rats (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 873-878 
    Details
    ISSN: 1573-904X
    Keywords: valproyl glycinamide ; valproyl glycine ; pharmacokinetics ; brain and liver distribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To investigate the disposition of valproyl glycinamide and valproyl glycine in rats and to compare it with that of valproic acid (VPA) and valpromide which were studied previously. Methods. The study was carried out by monitoring the brain and liver levels of valproyl glycinamide and valproyl glycine (as a function of time after iv dosing) in addition to the regular pharmacokinetic (PK) monitoring of plasma and urine levels of these compounds. Results. The following PK parameters were obtained for valproyl glycinamide and valproyl glycine, respectively: clearance, 7.1 and 16 ml/ min/kg; volume of distribution (Vss), 0.78 and 0.41 1/kg; half-life, 1.1 and 0.37 h; and mean residence time, 1.8 and 0.4 h. The ratios of AUCs of valproyl glycinamide of liver to plasma and brain to plasma were 0.70 and 0.66, respectively. The ratios of the AUCs of valproyl glycine of liver to plasma and brain to plasma were 0.19 and 0.02, respectively. Conclusions. Valproyl glycinamide distributes better in the brain than VPA, a fact which may contribute to its better anticonvulsant activity. Valproyl glycine was barely distributed in the brain, a fact which may explain its lack of anticonvulsant activity. In addition to the liver, the brain was found to be a minor metabolic site of the biotransformation of valproyl glycinamide to valproyl glycine.
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    Assessment of Dose Proportionality, Absolute Bioavailability, and Immunogenicity Response of CTLA4Ig (BMS-188667), a Novel Immunosuppressive Agent, Following Subcutaneous and Intravenous Administration to Rats (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 911-916 
    Details
    ISSN: 1573-904X
    Keywords: CTLA4Ig ; intravenous ; subcutaneous ; pharmacokinetics ; immunogenicity ; rats
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The objectives of this study were: to delineate the pharmacokinetics of CTLA4Ig in rats after single and multiple intravenous (IV) and subcutaneous (SC) doses; to assess the relationship of the pharmacokinetic parameters of CTLA4Ig vs dose; to calculate the SC absolute bioavailability; and to assess the antibody response of CTLA4Ig. Methods. A total of 48 (24 male and 24 female) Sprague Dawley rats were divided into eight treatments with 3 rats per gender in each group: a single dose of 10, 80, or 200 mg/kg of CTLA4Ig given either IV or SC and a repeated dose of 10 mg/kg (once every other day for 7 doses over 13 days) given either SC or IV. Serial blood samples were collected up to 43 days after single dose administration and up to 50 days following the administration of the last multiple dose on day 13. The serum concentration of CTLA4Ig and anti-CTLA4Ig antibodies were measured using ELISA assays. Results. After single IV doses, Cmax and AUCinf increased in a dose proportional manner; CL appeared to be dose independent, while both Vss and T1/2 increased as the administered dose increased. Following single SC doses, Cmax and AUCinf increased in a linear manner but not proportionally; mean Tmax values were prolonged but similar among the three dose levels, while T1/2 increased as the administered dose increased. The absolute SC bioavailability of CTLA4Ig decreased as the dose increased from 10 (62.5%), 80 (55.7%), and 200 mg/kg (41.1%). Comparison of the AUCtau values between the first and last doses suggested an accumulation (3.1−4.7) of CTLA4Ig. However, regardless of the route of dosing, AUCtau after the last dose were comparable to AUCinf values following the single dose. Anti-CTLA4Ig antibodies were detected at the 10 mg/kg dose level after single or multiple doses for both routes of administration. However, regardless of single or multiple doses, antibody titers were relatively greater for the SC compared to the IV administration. Conclusions. The key findings of this study were: (i) the elimination characteristics of CTLA4Ig were comparable between the SC and IV routes; (ii) the repeated dosing did not alter the pharmacokinetics of CTLA4Ig; (iii) the SC absolute bioavailability tended to decrease as the administered dose increased; and (iv) a greater formation of anti-CTLA4Ig antibodies was observed after SC compared to IV at a single 10 mg/kg dose level; however, after multiple dosing, the formation of antibodies from either of the two routes was relatively slower, and (v) during the study period, no antibodies were observed at either the 80 or 200 mg/kg dose levels regardless of the route of administration.
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    Studies on the Mechanism of Absorption of Depot Neuroleptics: Fluphenazine Decanoate in Sesame oil (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 1079-1084 
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    ISSN: 1573-904X
    Keywords: fluphenazine decanoate ; prodrug ; fluphenazine ; pharmacokinetics ; single dose
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of the present study was to investigate the pharmacokinetic characteristics of fluphenazine (FLU) and its decanoate (FLU-D) after intravenous and intramuscular administration to dogs. Methods. A group of four beagle dogs was used in all intravenous and intramuscular experiments, with washout periods of no less than three months between doses. Results. After intravenous FLU-D, the pharmacokinetics of the prodrug (mean ± SD) were as follows: Clearance (CL) 42.9 ± 6.3 L/h; terminal half-life (t1/2) 3.5 ± 0.8 h; volume of distribution (Vd) 216 ± 61 L. The fractional availability of FLU was 1.0 ± 0.2. After intravenous FLU, the volume of distribution of FLU (51 ± 17.8 L) was some 4 fold less than that of the prodrug. Simulations (Stella II) suggested that the rate limiting step was slow formation of FLU from the prodrug in the tissue compartment. After intramuscular FLU-D in sesame oil, the apparent t1/2 of FLU was 9.7 ± 2.0 days whereas after intramuscular FLU base in sesame oil, the apparent t1/2 was only 7.7 ± 3.4 h showing that the absorption of FLU itself from the intramuscular site and proximal lymph nodes is relatively rapid. Conclusions. The rate limiting step after intramuscular FLU-D appeared to be the slow partitioning of the prodrug out of the sesame oil at the injection site and in proximal lymph nodes.
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    Disposition Characteristics of Plasmid DNA in the Single-pass Rat Liver Perfusion System (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 599-603 
    Details
    ISSN: 1573-904X
    Keywords: plasmid DNA ; liver perfusion ; pharmacokinetics ; gene therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To define the hepatic uptake mechanism of a plasmid DNA, we quantitated the uptake of pCAT (plasmid DNA encoding chloramphenicol acetyltransferase reporter gene fused to simian virus 40 promoter), a model plasmid, after a single pass through the perfused rat liver using albumin- and erythrocyte-free Krebs-Ringer bicarbonate buffer (pH 7.4). Methods. [32P]pCAT was introduced momentarily into this system from the portal vein as a bolus input or constant infusion mode, and the outflow patterns and hepatic uptake were evaluated using statistical moment analysis. Results. The venous outflow samples had electrophoretic bands similar to that of the standard pCAT, suggesting that the plasmid is fairly stable in the perfusate during liver perfusion. In bolus experiments, pCAT was largely taken up by the liver and the uptake was decreased with increase in injected dose. Statistical moment analysis against outflow patterns demonstrated that the apparent volume of distribution of pCAT was greater than that of human serum albumin, indicating a significant reversible interaction with the tissues. The results of collagenase perfusion experiments suggest that the hepatic accumulation of pCAT occurred preferentially in the nonparenchymal cells (NPC). The amount of total recovery in the liver decreased substantially by preceding administration of polyinosinic acid, dextran sulfate, succinylated bovine serum albumin, but not by polycytidylic acid. This suggests that pC AT is taken up by the liver via scavenger receptors for polyanions on the NPC. In constant infusion experiments, the presence of 2,4-dinitrophenol and NH4C1 caused a significant increase in the outflow concentration of [32P]pCAT and decrease by half in the total hepatic recovery than that of plasmid DNA administered alone, suggesting that plasmid DNA may undergo internalization by the NPC. Conclusions. The liver plays an important role in the elimination of plasmid DNA and a successful delivery system will be required to avoid its recognition by the scavenger receptors on the liver NPC.
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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 
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    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016273907749
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  • 96
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    Influence of Different Fat Emulsion-Based Intravenous Formulations on the Pharmacokinetics and Pharmacodynamics of Propofol (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 442-448 
    Details
    ISSN: 1573-904X
    Keywords: propofol ; pharmacokinetics ; pharmacodynamics ; rats ; EEG ; fat emulsion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The influence of different intravenous formulations on the pharmacokinetics and pharmacodynamics of propofol was investigated using the effect on the EEG (11.5-30 Hz) as pharmacodynamic endpoint. Methods. Propofol was administered as an intravenous bolus infusion (30 mg/kg in 5 min) or as a continuous infusion (150 mg/kg in 5 hours) in chronically instrumented male rats. Propofol was formulated as a 1% emulsion in an Intralipid 10%®-like fat emulsion (Diprivan-10®, D) or as a 1%- or 6% emulsion in Lipofundin® MCT/LCT-10% (Pl% and P6%, respectively). EEG was recorded continuously and arterial blood samples were collected serially for the determination of propofol concentrations using HPLC. Results. Following bolus infusion, the pharmacokinetics of the various propofol emulsions could adequately be described by a two-compart-mental pharmacokinetic model. The average values for clearance (Cl), volume of distribution at steady-state (Vd,ss) and terminal half-life (t1/2, λ2) were 107 ± 4 ml/min/kg, 1.38 ± 0.06 l/kg and 16 ± 1 min, respectively (mean ± S.E., n = 22). No significant differences were observed between the three propofol formulations. After continuous infusion these values were 112 ± 11 ml/min/kg, 5.19 ± 0.41 l/kg and 45 ± 3 min, respectively (mean±S.E., n = 20) with again no statistically significant differences between the three propofol formulations. Comparison between the bolus- and the continuous infusion revealed a statistically significant difference for both Vd,ss and t1/2, λ2 (p 〈 0.05), whereas Cl remained unchanged. In all treatment groups infusion of propofol resulted in a burst-suppression type of EEG. A profound hysteresis loop was observed between blood concentrations and EEG effect for all formulations. The hysteresis was minimized by a semi-parametric method and resulted in a biphasic concentration-effect relationship of propofol that was described non-parametrically. For P6% a larger rate constant onset of drug effect (t,1/2, keo) was observed compared to the other propofol formulations (p〈0.05). Conclusions. The pharmacokinetics and pharmacodynamics of propofol are not affected by to a large extent the type of emulsion nor by the concentration of propofol in the intravenous formulation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011980432646
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  • 97
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    Distribution of a 20-Mer Phosphorothioate Oligonucleotide, CGP69846A (ISIS 5132), into Airway Leukocytes and Epithelial Cells Following Intratracheal Delivery to Brown-Norway Rats (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1542-1549 
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    ISSN: 1573-904X
    Keywords: antisense ; Brown-Norway rat ; oligodeoxynucleotide ; pulmonary delivery ; ISIS 2105 ; pharmacokinetics ; airway inflammation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To evaluate the pulmonary distribution of CGP69846A (ISIS 5132), a phosphorothioate oligonucleotide, following intra-tracheal (i.t.) instillation into Brown-Norway rats. Methods. The pharmacokinetic profile of [3H]-CGP69846A was investigated following i.t. instillation into both naïve and inflamed airways of Brown-Norway rats. The cellular distribution was determined using autoradiography, immunohistochemistry and flow cytometry/fluorescence microscopy, in inflamed airways. Results. CGP69846A displayed a dose-dependent lung retention following i.t. administration which was unaffected by local inflammation. Autoradiography and immunohistochemistry showed distribution to alveolar macrophages, eosinophils, bronchial and tracheal epithelium and alveolar cells. Studies with [FITCJ-CGP69846A demonstrated a preferential association of oligonucleotide with leukocytes in bronchial lavage fluid of: macrophages 〉 eosinophils = neutrophils 〉 〉 lymphocytes. Conclusions. The dose-dependency of lung retention together with cell-specific uptake suggests that the lung can be used as a local target for antisense molecules with potentially minimal systemic effects. Furthermore, the preferential targeting of macrophages and the airway epithelium by oligonucleotides may represent rational cellular targets for antisense therapeutics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015048419558
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  • 98
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    Electronic Resource
    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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  • 99
    Electronic Resource
    Electronic Resource
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011924631680
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  • 100
    Electronic Resource
    Electronic Resource
    Pharmacokinetic Features and Metabolism of Calphostin C, A Naturally Occurring Perylenequinone with Antileukemic Activity (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1003-1009 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; Calphostin C ; HPLC ; perylenequinone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To examine the pharmacokinetic features and metabolism of calphostin C, a naturally occurring perylenequinone with potent antileukemic activity. Methods. HPLC-based quantitative detection methods were used to measure calphostin C levels in lysates of leukemic cells and in plasma of mice treated with calphostin C. The plasma concentration-time data were analyzed using the WinNonlin program. In vitro esterases and a microsome P450 preparation in conjunction with a LC-MS(API-EI) system were used to study the metabolism of calphostin C. Results. An intracellular exposure level (AUC0−6h) of 257 μM·h was achieved after in vitro treatment of NALM-6 cells with calphostin C at a 5 μM final concentration in culture medium. After intraperitoneal (i.p.) injection of a 40 mg/kg nontoxic bolus dose of calphostin C, the estimated Cmax was 2.9 μM, which is higher than the effective in vitro concentration of calphostin C against leukemic cells. Drug absorption after i.p. administration was rapid with an absorption half-life of 24.2 min and the estimated tmax was 63.0 min. Calphostin C was cleared with an elimination half-life of 91.3 min. An inactive and smaller metabolite (calphostin B) was detected in plasma of calphostin C-treated mice with a tmax of 41.3 min. Esterase (but not P450) treatment of calphostin C in vitro yielded an inactive metabolite (calphostin B) of the same size and elution profile. Conclusions. Target plasma calphostin C concentrations of potent antileukemic activity can be reached in mice at nontoxic dose levels. This pilot pharmacokinetic study of calphostin C combined with the availability of the described quantitative HPLC method for its detection in cells and plasma provide the basis for future preclinical evaluation of calphostin C and its potential as an anti-leukemic drug.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018923430094
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