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  • Articles  (16)
  • Pharmacokinetics  (16)
  • Springer  (16)
  • American Institute of Physics (AIP)
  • Oxford University Press
  • Wiley
  • 1995-1999  (16)
  • 1999  (16)
  • Medicine  (16)
  • Physics
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  • Articles  (16)
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  • 1995-1999  (16)
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  • 1
    Electronic Resource
    Electronic Resource
    Sibutramine pharmacokinetics in young and elderly healthy subjects (1999)
    Springer
    European journal of clinical pharmacology 54 (1999), S. 847-849 
    Details
    ISSN: 1432-1041
    Keywords: Key words Sibutramine ; Pharmacokinetics ; Age
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To investigate the pharmacokinetics of the pharmacologically active metabolites of sibutramine (metabolites 1 and 2) in healthy young and elderly volunteers following a single oral dose of sibutramine. Methods: This was an open, parallel-group study completed by 12 young (six male, six female; mean age 24.0 years) and 12 elderly (six male, six female; mean age 70.3 years) healthy volunteers. Blood samples were taken at intervals up to 48 h post-dose. Plasma concentrations of metabolites were determined using HPLC-MS. Model-independent pharmacokinetic parameters of the two metabolites were compared for the two age groups. Results: The similarity of the plasma profiles of the two desmethyl metabolites showed that despite the possibility of reduced hepatic function due to age, the rate and extent of formation of these was the same in both young and elderly, i.e. sibutramine metabolism was not impaired in elderly subjects. There were also no significant differences in elimination of metabolite 2 between groups, although the elderly group showed a slight trend for a reduction in kel. Conclusions: The pharmacokinetics of the two pharmacologically active metabolites of sibutramine (metabolites 1 and 2) were not significantly different between the young and elderly groups in this study. Based on this information, a similar dosing regimen would be appropriate for both the young and elderly.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050565
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  • 2
    Electronic Resource
    Electronic Resource
    Irbesartan does not affect the steady-state pharmacodynamics and pharmacokinetics of warfarin (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 593-598 
    Details
    ISSN: 1432-1041
    Keywords: Key words Irbesartan ; Warfarin ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objectives: To determine whether the initiation or titration of irbesartan alters the pharmacodynamics and/or pharmacokinetics of warfarin in a clinically significant manner, thereby requiring additional monitoring of the anticoagulant effect of warfarin. Methods: Daily doses of warfarin were administered to 16 healthy males for 21 days (10 mg on day 1 and 2.5–10 mg on days 2–21). Irbesartan (300 mg/day) or placebo was concomitantly administered on days 15–21. The pharmacodynamic parameters prothrombin time (PT) and prothrombin time ratio (PTR) were evaluated throughout the study. Plasma and urine samples were collected before and up to 24 h after administration on days 14, 15 and 21 for the determination of the maximum concentration (Cmax), time to reach Cmax (tmax), the area under the concentration–time curve (AUC) of S-warfarin and the cumulative urinary excretion of warfarin and its metabolites. Pre-dose plasma samples were also collected to determine the Cmin of S-warfarin (days 12, 13, 14 and 21) and irbesartan (days 19, 20 and 21). Results: Analysis of PTR data revealed no significant difference between the group mean PTR values at day 22 and those at day 15 (P=0.699). S-warfarin concentrations in plasma and urine, as well as the urinary concentrations of the metabolites of warfarin, were not affected by concomitant single- or multiple-dose administration of irbesartan. Plasma Cmin concentrations of S-warfarin and irbesartan were also not affected. Conclusions: No clinically important effect of irbesartan on the pharmacodynamics and pharmacokinetics of warfarin are likely to occur during concomitant administration; therefore, neither a dosage adjustment of irbesartan or warfarin nor any additional monitoring of the anticoagulant effect of warfarin is necessary.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050678
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  • 3
    Electronic Resource
    Electronic Resource
    Effect of orlistat on blood cyclosporin concentration in an obese heart transplant patient (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 667-669 
    Details
    ISSN: 1432-1041
    Keywords: Key words Cyclosporin ; Orlistat ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: We detected markedly decreased cyclosporin blood levels in a heart-transplanted patient after the gastrointestinal lipase inhibitor orlistat was accidentally added to the treatment program to control for his obesity. Therefore, we determined cyclosporin plasma concentration time kinetics with and without orlistat reexposition in this patient. Methods: Plasma concentration time kinetics of whole blood cyclosporin levels in an obese heart-transplant patient were measured using a standard monoclonal fluorescence polarisation immunoassay. Results were obtained in hourly intervals up to 12 h without and with co-therapy of 3 × 120 mg orlistat (Xenical, Roche Ltd., Switzerland). The orlistat re-exposition was started the day before taking blood samples. Results: Cyclosporin trough levels (98 ng/ml vs 52 ng/ml), maximum concentrations (532 ng/ml vs 74 ng/ml) and the area under the blood drug concentration-time curve (2832 ng h ml−1 vs 700 ng h ml−1) were greatly reduced with orlistat. Conclusions: Orlistat markedly decreased blood cyclosporin concentrations, possibly due to an interference with its absorption in the small intestine. To avoid potential dangerous under-immunosuppression, orlistat should not be used in patients taking cyclosporin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050690
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  • 4
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamics of candesartan cilexetil in patients with normal to severely impaired renal function (1999)
    Springer
    European journal of clinical pharmacology 54 (1999), S. 953-958 
    Details
    ISSN: 1432-1041
    Keywords: Key words AT1 receptor antagonist ; Blood pressure ; Candesartan cilexetil ; Candesartan ; Pharmacokinetics ; Renin angiotensin system
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: We studied the pharmacokinetics and pharmacodynamics of single and multiple doses of candesartan cilexetil 8 mg per day in hypertensive patients with different degrees of renal function impairment. Candesartan is an angiotensin II subtype 1 (AT1) receptor antagonist that is administered orally as candesartan cilexetil which is converted in the active compound. Methods: Twenty-three patients were included, divided into groups according to creatinine clearance (cr cl. group A 〉60 nl · min−1 · 1.73 m−2, group B 30–60 ml · min−1 · 1.73 m−2 and group C 15–30 ml · min−1 · 1.73 m−2). Results: Trough serum concentrations of candesartan were higher in group C compared with group A. The values did not increase after multiple dosing, indicating absence of accumulation. There was a significant negative correlation between the area under the concentration-time curve extrapolated to time infinity (AUCinf) and the glomerular filtration rate (GFR) indicating a lower renal clearance of candesartan in patients with impaired renal function. The onset of haemodynamic and hormonal effects was gradual. During the single-dose study blood pressure as well as plasma renin activity (PRA) and angiotensin II were unchanged at peak. At day 5 of the multiple-dose study blood pressure was lower and both PRA and angiotensin II were higher compared with baseline. Conclusion: Although serum trough levels increased during repeated administration and half-life was higher in patients with impaired renal function, candesartan cilexetil at a dose of 8 mg per day does not lead to drug accumulation in these patients. This dose is effective in lowering blood pressure and appears to be suitable for patients with renal function impairment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050581
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  • 5
    Electronic Resource
    Electronic Resource
    Limited-sampling strategy models for estimating the area under the plasma concentration–time curve for amlodipine (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 651-657 
    Details
    ISSN: 1432-1041
    Keywords: Key words Amlodipine ; Limited-sampling models ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Develop and validate limited-sampling strategy (LSS) models for estimating the area under the plasma concentration versus time curve (AUC) of amlodipine, using data from a bioequivalence study. Methods: Sixteen healthy volunteers received single 5-mg oral doses of amlodipine, as reference or test formulation, at a 14-day interval, in a randomized, crossover protocol. Plasma concentrations of amlodipine (n = 288), measured by mass spectrometry, were used to develop LSS models. Results: Linear regression analysis of the AUC0–72 and a “jack-knife” validation procedure revealed that LSS models based on two sampling times (12 h and 48 h) predict accurately (R2 = 0.99; bias〈0.01%; precision = 0.03%) the AUC0–72 of amlodipine for each formulation. Validation tests indicate that the 2-point LSS model developed for the reference formulation predicts accurately (R2〉0.90): (a) the individual AUC0–72 for the test formulation in the same group of volunteers; (b) the individual AUC0–72 for the same reference formulation in another bioequivalence study in Brazilian volunteers; (c) the average AUC0–72 reported in seven additional international studies performed under protocols similar to the present investigation; (d) the individual AUC0–72 corresponding to concentration data points provided by a first-order compartmental pharmacokinetic model, when the relative values of either the absorption rate (K abs) or the bioavailability (F) model parameters were set at 0.85 or 0.6, of their respective original values. Conclusions: The 2-point LSS models developed in the current study predict accurately the AUC of amlodipine under a variety of experimental conditions and, thus, may be valuable for exploring the relationships between the pharmacokinetics and pharmacodynamics of this calcium antagonist, at reduced costs of sample acquisition and analysis, and avoiding sampling at “unsociable” hours.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050688
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  • 6
    Electronic Resource
    Electronic Resource
    Bioavailability of intranasal formulations of dihydroergotamine (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 677-680 
    Details
    ISSN: 1432-1041
    Keywords: Key words Dihydroergotamine ; Absorption ; Intranasal ; Randomly methylated β-cyclodextrin (RAMEB) ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: A comparison of the pharmacokinetic properties of two novel intranasal preparations of dihydroergotamine mesilate (DHEM) with a commercially available intranasal preparation. Methods: Two intranasal formulations of DHEM in combination with randomly methylated β-cyclodextrin (RAMEB) were prepared. Subsequently, in an open, randomised, crossover study in nine healthy volunteers, the following medication was administered: 2 mg DHEM/2% RAMEB nasal spray ( =two puffs of 100 μl); 2 mg DHEM/4 mg RAMEB nasal powder; 2 mg Diergo nasal spray ( =four puffs of 125 μl); 0.5 mg DHEM i.m., and 2 mg DHEM solution p.o. Results: No statistically significant differences were found in maximum plasma concentration (Cmax), time to reach Cmax (tmax), area under plasma concentration–time curve (AUC0–8 h), Frel(t=8 h) and Cmax/ AUC(t=8 h) for the three intranasal preparations. The relative bioavailabilities of the DHEM/RAMEB nasal spray, the DHEM/RAMEB nasal powder and the commercially available DHEM nasal spray were 25%, 19% and 21%, respectively, in comparison with i.m. administration. The relative bioavailability after oral administration was 8%. Conclusion: The pharmacokinetic properties of the novel intranasal preparations are not significantly different from the commercially available nasal spray. Advantages of the DHEM/RAMEB nasal spray are (1) less complicated handling, (2) reduction of the number of puffs and (3) a preference by the volunteers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050692
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  • 7
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of oxypolygelatine in healthy volunteers (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 49-51 
    Details
    ISSN: 1432-1041
    Keywords: Key words Oxypolygelatine ; Pharmacokinetics ; Healthy volunteers ; Tolerability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective/methods: The pharmacokinetics of the plasma substitute oxypolygelatine (OPG) were studied in 12 healthy volunteers after single-dose administration of 27 ml · kg−1 body weight, with a maximum of 2000 ml. OPG was determined in plasma and urine over 48 h after the infusion. Peak plasma OPG concentrations at the end of the infusion were determined to 4.600 (623) μg · ml−1, the area under the plasma concentration/time curve (AUC0∞) was calculated to 70.135 (15.861) μg · h · ml−1. Results: The model-independently calculated volume of distribution came to 23.1 (4.8) l with a clearance total is (Cltot) of 24.6 (6.8) ml · min−1. The initial half-life according to a three-compartment model came to 0.3 (0.2) h, followed by a distribution half-life of 3.1 (2.6) h and a terminal elimination half-life of 13.4 (2.2) h. Cumulative urinary excretion of OPG was 64% after 48 h. Conclusion: This low recovery rate may be explained by the distribution of OPG into the extravascular space and subsequent degradation in tissue sites.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050591
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  • 8
    Electronic Resource
    Electronic Resource
    Absence of interaction between erythromycin and a single dose of clozapine (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 221-226 
    Details
    ISSN: 1432-1041
    Keywords: Key words Clozapine ; Erythromycin ; CYP3A4 ; Pharmacokinetics ; Drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To study the suggested pharmacokinetic interaction between erythromycin, a strong inhibitor of CYP3A4, and clozapine. Methods: Twelve healthy male volunteers received a single dose of 12.5 mg of clozapine alone or in combination with a daily dose of 1500 mg erythromycin in a randomised crossover study. Clozapine and its metabolites clozapine-N-oxide and desmethyl-clozapine were measured in serum samples which were collected during a 48 h period and in a sample of the urine secreted over the interval 0–12 h. Results: There were no significant differences in mean area under the serum concentration time curves (1348 (633) nmol h · 1−1 in the control phase and 1180 (659) nmol h · 1−1 in the erythromycin phase), terminal half-lives (19 (13) h and 15 (6) h, respectively), peak serum concentrations (92 (53) nmol · 1−1 and 77 (40) nmol · 1−1, respectively), time to peak serum concentrations (1.4 (0.7) h and 1.5 (1.0) h, respectively) or apparent oral clearances of clozapine (34 (15) l · h−1 and 46 (37) l · h−1, respectively). There were no significant differences in partial metabolic clearances to clozapine-N-oxide (5.1 (3.6) l · h−1 and 7.8 (9.4) l · h−1, respectively) or to desmethyl-clozapine (1.5 (1.3) l · h−1 and 1.8 (1.7) l · h−1, respectively) or in renal clearances of clozapine (0.8 (0.5) l · h−1 and 1.0 (0.7) l · h−1, respectively) between the two phases. Conclusion: These results demonstrate that erythromycin at a clinically relevant dosage does not inhibit the metabolism of clozapine. Hence, CYP3A4 seems to be of minor importance in the disposition of clozapine in humans at least when clozapine is taken at a low single dose.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050621
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  • 9
    Electronic Resource
    Electronic Resource
    Lack of influence of menstrual cycle and premenstrual syndrome diagnosis on pregnanolone pharmacokinetics (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 125-130 
    Details
    ISSN: 1432-1041
    Keywords: Key words Pregnanolone ; Pharmacokinetics ; Premenstrual syndrome
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Pregnanolone is a 3α-hydroxylated-5β-reduced metabolite of the female sex steroid hormone progesterone. The compound is currently being evaluated for anaesthetic purposes. Previous studies have indicated a differential physiological response across the menstrual cycle and a different response in patients with premenstrual syndrome (PMS). This study was undertaken to determine whether hormonal changes during the menstrual cycle influence pregnanolone pharmacokinetics and to compare PMS diagnosis-related differences in pregnanolone pharmacokinetics. Methods: Seven patients with premenstrual syndrome and seven female controls were given three increasing doses of pregnanolone in the follicular and luteal phase of the menstrual cycle. Results: Mean pregnanolone elimination half-life varied between 28.4 min and 31.8 min and clearance between 59.6 ml · min−1 · kg−1 and 64.0 ml · min−1 · kg−1, depending on diagnostic group and cycle phase. No significant differences in pregnanolone pharmacokinetic properties were found between PMS patients and controls in either phase of the menstrual cycle. Furthermore, no differences in pharmacokinetic variables were detected between cycle phases. Conclusion: Pregnanolone pharmacokinetics do not differ between follicular and luteal phase of the menstrual cycle, nor between PMS patients and control subjects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050606
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  • 10
    Electronic Resource
    Electronic Resource
    Development of a general method of limited sampling for the determination of AUC for a drug that displays two-compartment pharmacokinetics (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 213-219 
    Details
    ISSN: 1432-1041
    Keywords: Key words Limited sampling ; Area under the curve ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objectives: To develop a method of limited sampling that would enable accurate estimation of the area under the concentration time curve (AUC) when using the log trapezoidal method. Methods: A series of datasets were simulated. Each dataset comprised 1000 subjects. Each subject was “administered” an intravenous bolus dose of a drug that displays two compartment pharmacokinetics. In the first series of simulations, a variety of combinations of the number of sampling times (K) and number of replicate measurements (R) at each of these times were tested, where K × R = 12 (i.e. N = 12). The times that each of the K samples were taken were chosen to be those that divided the AUC into K − 1 trapezoids of equal area. The concentration-time curves were estimated based on a priori estimates of the population parameters. The best combination of K and R was tested under various conditions of parameter variability and assay variability. The combinations were compared with a conventional sampling strategy, where N = 12, K = 12 (R = 1). Results: The combination K = 4 and R = 3 proved to be the “best”. It had similar accuracy to the conventional method. The best limited sampling combination was superior to the conventional method when assay variability was high (CV = 30%), was similar when assay variability was 15%, but the conventional method became statistically superior when assay variability was 7.5% or less. The accuracy of the best limited sampling combination was inversely related to the parameter variability. If K was set to 4 and R allowed to increase to 6 (i.e. N≠ 12), there was no further gain in accuracy. Conclusion: The proposed method of limited sampling is at least as accurate as the conventional intensive sampling technique, but more efficient in terms of sampling.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050620
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  • 11
    Electronic Resource
    Electronic Resource
    Renal handling of drugs in the healthy elderly Creatinine clearance underestimates renal function and pharmacokinetics remain virtually unchanged (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 205-211 
    Details
    ISSN: 1432-1041
    Keywords: Key words Elderly ; Pharmacokinetics ; Renal function
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: It is commonly assumed that renal function, and in parallel the excretion of drugs, is considerably reduced in the elderly. Endogenous creatinine clearance or indirect estimates of this parameter are generally recommended for adapting drug dosage. The present study evaluates the validity of both assumptions. Methods: We compared pharmacokinetics (and pharmacodynamics) of 50 mg atenolol, 800 mg piracetam and 25 mg hydrochlorothiazide plus 50 mg triamterene in ten healthy young [25 (2) years] and 11 healthy elderly subjects [68 (5) years]. Inulin (Cin) and para-aminohippurate [PAH (CPAH)] clearance (infusion clearance technique), endogenous (CCr) and calculated (Cockroft-Gault) creatinine clearance, analysis of drugs and their metabolites (HPLC), were performed. Renal haemodynamics and the pharmacokinetics of β-adrenergic blocking agent, diuretics and the nootropic agent piracetam, respectively, were measured on separate days. Results: Cin was significantly (P 〈 0.01) lower in the healthy elderly subjects [104 (12) vs 120 (14) ml · min−2 · 1.73 m−2 in the young], but remained within the normal range (〉90 ml · min−2 · 1.73 m−2). In contrast, CCr was even lower in healthy elderly subjects [95 (24) vs 121 (20) ml · min−1 in the young], and the Cockroft-Gault clearance underestimated true glomerular filtration rate (GFR) even more seriously [74 (17) vs 122 (16) ml · min−1]. For atenolol the mean area under the curve (AUC) was similar in both groups [3.16 (0.48) μg · h−1 · ml−1 in the elderly vs 3.01 (0.30) in the young], as was the mean maximal plasma concentration [0.42 (0.07) vs 0.44 (0.06) μg · ml−1], but the proportion of the drug excreted in urine was marginally (P 〈 0.025) lower in the elderly. Similar results were obtained for hydrochlorothiazide, whereas no marked differences between the groups were found for triamterene and its metabolite. Furthermore, the pharmacodynamic action of diuretics was not significantly altered in the elderly. Conclusions: The true GFR of the healthy elderly remains within the normal range and is underestimated by creatinine clearance and more so by its surrogate (Cockroft-Gault clearance). In parallel, pharmacokinetics of renally excreted drugs are not affected in the healthy elderly to a clinically significant extent. For drugs with a narrow therapeutic window, indirect estimates of GFR appear to be an unreliable means for calculating correct dosage in the elderly.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050619
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  • 12
    Electronic Resource
    Electronic Resource
    Population pharmacokinetic analysis of pirmenol in healthy volunteers and patients with arrhythmia (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 77-78 
    Details
    ISSN: 1432-1041
    Keywords: Key words Pirmenol ; Arrhythmia ; 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/s002280050596
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  • 13
    Electronic Resource
    Electronic Resource
    Grapefruit juice has no effect on quinine pharmacokinetics (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 393-398 
    Details
    ISSN: 1432-1041
    Keywords: Key words Grapefruit juice ; Quinine ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: As quinine is mainly metabolised by human liver CYP3A4 and grapefruit juice inhibits CYP3A4, the effect of grapefruit juice on the pharmacokinetics of quinine following a single oral dose of 600 mg quinine sulphate was investigated. Methods: The study was carried out in ten healthy volunteers using a randomised cross-over design. Subjects were studied on three occasions, with a washout period of 2 weeks. During each period, subjects received a pretreatment of 200 ml orange juice (control), full-strength grapefruit juice or half-strength grapefruit juice twice daily for 5 days. On day 6, the subjects were given a single oral dose of 600 mg quinine sulphate with 200 ml of one of the juices. Plasma and urine samples for measurement of quinine and its major metabolite, 3-hydroxyquinine, were collected over a 48-h period and analysed by means of a high-performance liquid chromatography method. Results: The intake of grapefruit juice did not significantly alter the oral pharmacokinetics of quinine. There were no significant differences among the three treatment periods with regard to pharmacokinetic parameters of quinine, including the peak plasma drug concentration (Cmax), the time to reach Cmax (tmax), the terminal elimination half-life (t1/2), the area under the concentration–time curve and the apparent oral clearance. The pharmacokinetics of the 3-hydroxyquinine metabolite were slightly changed when volunteers received grapefruit juice. The mean Cmax of the metabolite (0.25 ± 0.09 mg l−1, mean ± SD) while subjects received full-strength grapefruit juice was significantly less than during the control period (0.31 ± 0.06 mg l−1, P 〈 0.05) and during the intake of half-strength grapefruit juice (0.31 ± 0.07 mg l−1, P 〈 0.05). Conclusion: These results suggest that there is no significant interaction between the parent compound quinine and grapefruit juice, so it is not necessary to advise patients against ingesting grapefruit juice at the same time that they take quinine. Since quinine is a low clearance drug with a relatively high oral bioavailability, and is primarily metabolised by human liver CYP3A4, the lack of effect of grapefruit juice on quinine pharmacokinetics supports the view that the site of CYP inhibition by grapefruit juice is mainly in the gut.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050646
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  • 14
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of oral entacapone after frequent multiple dosing and effects on levodopa disposition (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 461-467 
    Details
    ISSN: 1432-1041
    Keywords: Key words Entacapone ; Levodopa ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Entacapone is a peripherally acting catechol O-methyltransferase (COMT) inhibitor used as an adjunct to each daily levodopa/dopa decarboxylase (DDC) inhibitor dose in the treatment of Parkinson's disease. Parkinsonian patients with advanced disease and motor fluctuations take several doses of levodopa daily, due to the short action of levodopa in this patient population. The present study was conducted in order to evaluate the pharmacokinetics of entacapone after multiple dosing and the pattern of COMT inhibition in erythrocytes during the first day of dosing as well as during steady state. Furthermore, the disposition of plasma levodopa and carbidopa was studied after a single dose of levodopa/carbidopa during the same conditions. Methods: Twelve healthy male volunteers received 200 mg entacapone eight times daily during study day 1 and day 6 at 2-h intervals from 0800 hours to 2200 hours. During days 3, 4 and 5, 200 mg of entacapone was taken ten times daily, from 0800 hours to 0200 hours on the following day. One levodopa/carbidopa tablet (100/25 mg) was taken on study day 1 and day 6 at 1000 hours. Plasma entacapone concentrations and erythrocyte COMT activities were measured frequently on study days 1–2 and 6–7, and twice daily on study days 3–5. Pharmacokinetic parameters calculated from plasma drug concentrations on days 1–2 and 6–7 were compared with each other. Results: There were no differences in maximal plasma concentration (Cmax), time to maximal drug concentration in plasma (tmax), elimination half-life (t1/2) and area under the plasma concentration–time curve (AUC) of entacapone between day 1 and day 6. The mean t1/2 values of entacapone were 1.3 h and 1.8 h during the first and sixth days, respectively; the difference was not significant. No signs of accumulation of entacapone were noted after the first day. Entacapone reduced erythrocyte COMT activity after the first dose, and this effect was quite stable during frequent dosing. There were no indications of accumulation of COMT inhibition during frequent dosing of entacapone. There were no between-day differences in Cmax, t1/2 (2.4 h on days 1–2 and 2.3 h on days 6–7) or AUC of levodopa, whereas tmax occurred at 0.8 h on day 1 and at 1.2 h on day 6 (P = 0.03). There were no between-day differences in the pharmacokinetic parameters (Cmax, tmax and AUC) of carbidopa. Conclusion: Even when dosed frequently, there are neither indications of accumulation of entacapone nor of its COMT inhibiting activity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050657
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  • 15
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    Electronic Resource
    The effect of short-term dipyrone administration on cyclosporin pharmacokinetics (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 475-478 
    Details
    ISSN: 1432-1041
    Keywords: Key words Cyclosporin ; Dipyrone ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Background: A large number of drugs have been shown to affect the metabolism of cyclosporin A (CSA) and, since cyclosporin is characterized by a narrow therapeutic range, the consequences of such drug interactions may often be of clinical importance. Objective: To evaluate the effect of short-term administration of dipyrone on steady state CSA pharmacokinetics. Methods: Six kidney- and two heart-transplanted patients on chronic CSA therapy participated in this study, which consisted of two 4-day study periods separated by 3-week washout periods. The patients received, in addition to their usual drugs, dipyrone 500 mg or placebo t.i.d., as identical-looking tablets, and the order of administration was randomized. CSA concentrations were measured in whole blood by means of radio-immunoassay (CYCLO-Trac SP) daily during the study periods and periodically over 24 h on the fourth study day. Results: CSA concentrations over time were reduced after dipyrone (ANOVA, P 〈 0.01), but statistical significance was noted only at 2, 4, 5 and 10 h after drug intake (P 〈 0.05). Peak CSA concentration was not altered by dipyrone, but the time required to reach maximal concentration was longer with dipyrone treatment than with the placebo (3.8 ± 2.6 h vs 2.1 ± 0.6 h, P 〈 0.05). No consistent changes were noted for CSA trough level, elimination half-life and area under the concentration–time curve from 0 h to 12 h. Separate analysis of the kidney transplanted patients yielded similar results. Conclusions: Short-term administration of dipyrone is associated with a mild decrease in CSA blood concentration, which is most prominent in the first few hours after drug intake. In practice, no dose adjustment of CSA seems to be indicated during a short course of dipyrone treatment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050659
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  • 16
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    Electronic Resource
    A novel therapeutic trial of homogentisic aciduria in a murine model of alkaptonuria (1999)
    Springer
    Journal of human genetics 44 (1999), S. 79-84 
    Details
    ISSN: 1435-232X
    Keywords: Key words Alkaptonuria ; Homogentisic acid ; Treatment ; NTBC ; Murine model ; Pharmacokinetics ; Inborn error of metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Alkaptonuria is a rare autosomal recessive disorder characterized by homogentisic aciduria, ochronosis, and arthritis. Although a deficiency of homogentisic acid 1,2-dioxygenase has recently been confirmed at the molecular level, no effective treatment regimen has yet been developed for this disorder. In the present study, 2(-2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), a potent inhibitor of p-hydroxyphenylpyruvate dioxygenase (which catalyzes the formation of homogentisic acid from p-hydroxyphenylpyruvic acid) was adopted as a possible therapeutic agent for alkaptonuria. NTBC dose-dependently reduced the urinary output of homogentisic acid in a murine model of alkaptonuria that had been created with ethylnitrosourea. These findings suggest that NTBC may be the first potent pharmacotherapeutic agent for alkaptonuria.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s100380050114
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