摘要:

Clinical Pharmacology and Therapeutics(1994)56,117–121; doi:10.1038/clpt.1994.1

ISSN:0009-9236    

DOI:10.1038/clpt.1994.112

年代:1994

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1994)56,122–124; doi:10.1038/clpt.1994.1

ISSN:0009-9236    

DOI:10.1038/clpt.1994.113

年代:1994

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1994)56,125–126; doi:10.1038/clpt.1994.1

ISSN:0009-9236    

DOI:10.1038/clpt.1994.114

年代:1994

数据来源: WILEY

摘要:

The objective of this study was to determine the potential role of circulating testosterone and estradiol in regulation of the activity of the sex‐dependent pathways of propranolol metabolism (i.e., α‐naphthoxylactic acid and propranolol glucuronide). The pharmacokinetics of a single 80 mg oral dose of propranolol and the plasma levels of the sex steroid hormones were therefore determined in normal volunteers. In 33 young men there was a positive correlation between the testosterone levels and the propranolol clearances through both α‐naphthoxylactic acid (p<0.001) and propranolol glucuronide (p<0.002), as well as the total clearance (p<0.05), but not through aromatic ring hydroxylation. Testosterone cypionate administration led to an increased clearance of propranolol through α‐naphthoxylactic acid in nine of the 11 men studied, further supporting a stimulatory effect of testosterone on propranolol metabolism. In 23 young women there was no significant association between the circulating levels of either estradiol or testosterone and any of the clearances of propranolol. These observations may be clinically relevant for propranolol therapy and may provide improved insight into the influence of gender and circulating gonadal hormones on drug metabolism in humans.Clinical Pharmacology and Therapeutics(1994)56,127–132; doi:10.1038/

ISSN:0009-9236    

DOI:10.1038/clpt.1994.115

年代:1994

数据来源: WILEY

摘要:

The effects of probenecid (2 gm) on the pharmacokinetics, pharmacodynamics, and uricosuric effects of adinazolam andN‐desmethyladinazolam were assessed after single dose administration of adinazolam mesylate sustained‐release tablets (60 mg) in a randomized, four‐way crossover, double‐blind study involving 16 healthy male volunteers. Probenecid decreased adinazolam oral clearance, renalN‐desmethyladinazolam clearance, and the amount ofN‐desmethyladinazolam excreted in the urine. Probenecid increased theN‐desmethyladmazolam/adinazolam AUC ratio, adinazolam maximum concentration (Cmax),N‐desmethyladinazolam Cmax, andN‐desmethyladinazolam time to reach Cmax. Uric acid renal clearance was increased significantly by adinazolam or probenecid administration compared with placebo; however, coadministration of adinazolam plus probenecid had no additive effect on uric acid clearance. Psychomotor performance was decreased in the adinazolam plus probenecid treatment compared with the adinazolam treatment. Probenecid potentiated the psychomotor effects of adinazolam after coadministration of the compounds, predominantly because of alterations inN‐desmethyladinazolam pharmacokinetics. Therefore the adinazolam dose may need to be reduced when coadministered with probenecid.Clinical Pharmacology and Therapeutics(1994)56,133–141; doi

ISSN:0009-9236    

DOI:10.1038/clpt.1994.116

年代:1994

数据来源: WILEY

摘要:

We examined dapsoneN‐acetylation and metoprolol α‐hydroxylation and S‐mephenytoin 4‐hydroxylation phenotypings using the respective test probes (dapsone and racemic metoprolol and mephenytoin) administered separately and in a cocktail manner to an Indonesian subject group (n= 30). After ascertaining that the separate and cocktail phenotyping tests of the probe drugs correlated with each other (allrsvalues>0.84;p<0.001), the cocktail phenotyping assessment was extended to the other 74 Indonesians. In a total of 104 Indonesians phenotyped with the cocktail test, a visual antimode was apparent only in the dapsoneN‐acetylation andS‐mephenytoin 4‐hydroxylation polymorphisms: the frequencies of slow acetylators and poor hydroxylators were 43.3% (95% confidence interval, 33.7% to 52.8%) and 15.4% (95% confidence interval, 8.5% to 22.3%), respectively. The distribution histogram and pro‐bit plots of the metabolic ratio of metoprolol gave no clear evidence for bimodality, and therefore no poor α‐hydroxylator of metoprolol was considered to exist in the present sample size. The findings indicate that the Indonesian subjects have a greater incidence of slow acetylator phenotype compared with Japanese and Chinese, as well as a frequency of poor metabolizer phenotype ofS‐mephenytoin similar to that of Korean and Chinese subjects. They resemble an African population (Nigerians) in metoprolol α‐hydroxylation polymorphism, with no apparent antimode derived from white populations.Clinical Pharmacology and Therapeutics(1994)56,142–153

ISSN:0009-9236    

DOI:10.1038/clpt.1994.117

年代:1994

数据来源: WILEY

摘要:

The pharmacokinetics of oral gabapentin (400 mg) was studied in normal subjects and in subjects with various degrees of renal function. Sixty subjects participated in this three‐center study. None of the subjects were receiving hemodialysis. Plasma and urine samples were collected for up to 264 hours after dosing, and concentrations of gabapentin were determined by high performance liquid chromatography. Apparent oral plasma clearance (CL/F) and renal clearance (CLR) of gabapentin decreased and maximum plasma concentration, time to reach maximum concentration, and half‐life values increased as renal function diminished. GabapentinCL/Fand CLRwere linearly correlated with creatinine clearance. Total urinary recovery of unchanged drug was comparable in all subjects, indicating that the extent of drug absorption was unaffected by renal function. There was no evidence of gabapentin metabolism even in subjects with severe renal impairment. In summary, impaired renal function results in higher plasma gabapentin concentrations, longer elimination half‐lives, and reducedCL/Fand CLRvalues. Based on pharmacokinetic considerations, it appears that the dosing regimen of gabapentin in subjects with renal impairment may be adjusted on the basis of creatinine clearance.Clinical Pharmacology and Therapeutics(1994)56,154–159; doi:10.1038/clpt.

ISSN:0009-9236    

DOI:10.1038/clpt.1994.118

年代:1994

数据来源: WILEY

摘要:

Enalapril and enalaprilat concentrations were measured after enalapril maleate (0.05 to 0.3 mg/kg) was administered orally to 12 pediatric patients (age range, 10 days to 6½ years) with congestive heart failure caused by congenital heart disease and compared with those obtained from seven normal adults (age range, 21 to 39 years). When normalized to the oral 1 mg/m2dose of enalapril maleate, the mean ± SD area under the serum concentration–time curve (AUC) of enalaprilat, a pharmacologically active angiotensin‐converting enzyme inhibitor, did not differ significantly between the pediatric group aged>20 days and adult group (83.1 ± 47.0 versus 64.6 ± 17.8 ng · hr/ml per 1 mg/m2). When normalized to the oral 0.1 mg/kg dose, the mean AUC was significantly (p<0.05) smaller in this pediatric group than in the adult group (138.4 ± 69.2 versus 245.7 ± 61.8 ng · hr/ml per 0.1 mg/kg). The AUC observed in three younger (age20 days. The mean AUC ratio of enalaprilat to enalapril was significantly (p20 days. The oral dosage should be much reduced in infants with congestive heart failure aged20 days. The biotransformation capacity of enalapril to enalaprilat appears to be abruptly matured during an early developmental period.Clinical Pharmacology and Therapeutics(1994)56,160–168; doi:10.10

ISSN:0009-9236    

DOI:10.1038/clpt.1994.119

年代:1994

数据来源: WILEY

摘要:

ObjectiveTo determine population pharmacokinetic parameters of vancomycin in neonates.MethodsThis was a retrospective design, with prospective validation.Two hundred ten sequential neonates were evaluated at the neonatal intensive care units of Minneapolis Children's Medical Center and Children's Hospital of St. Paul. Five hundred twenty serum concentrations from 192 patients were included. A mean ± SD gestational age of 29.5 ± 5.1 weeks, postnatal age of 16.5 ± 19.6 days, and dosing weight of 1492 ± 1053 gm described the population. Thirty additional patients were studied for validation. Dosing, serum concentrations, and 28 covariates were collected. Data were evaluated with NONMEM. Forward selection and backward elimination regression identified significant covariates. One‐ and two‐compartment population pharmacokinetic parameters and predictive performance of the models were measured.ResultsTwo‐compartment final regression equations were as follows: Clearance (CL) = 0.0590 L/kg/hr (multiplied by 0.460 if exposed to dopamine and 0.643 if gestational age was ≤32 weeks), central volume (Vc) = 0.440 L/kg, intercompartmental clearance (Q) = 0.0313 L/hr/kg, and steady‐state volume of distribution (Vss) = 0.764 L/kg. Interindividual variability was 40.6% for CL, 54.1% for Vss, and 16.8% for Vc. Residual variability was 3.3 µg/ml. One‐compartment final regression equations were: CL = 0.0626 L/kg/hr (multiplied by 0.455 if exposed to dopamine and 0.656 if gestational age was ≤32 weeks), and Vd= 0.496 L/kg. Differences in relative performance were insignificant by use of one‐ or two‐compartment parameters.ConclusionsGestational age ≤32 weeks and concurrent use of dopamine were significant factors in prediction of vancomycin clearance, α Half‐lives of 2.8 to 3.7 hours and β half‐lives of 13.4 to 33.7 hours suggest that some individuals in this neonatal population have considerably longer half‐live

ISSN:0009-9236    

DOI:10.1038/clpt.1994.120

年代:1994

数据来源: WILEY

摘要:

The pharmacokinetics of mianserin and its main metabolite desmethylmianserin were studied in poor and extensive metabolizers of debrisoquin and ofS‐mephenytoin after a single oral dose of racemic mianserin. The debrisoquin metabolic ratio (MR) correlated significantly with area under the serum concentration–time curves (AUC) for (±)‐mianserin and (±)‐desmethylmianserin. Enantioselective high‐performance liquid Chromatographie analysis of mianserin showed that debrisoquin MR was related to AUC(0–12) forS(+)‐mianserin (rs= 0.87;p= 0.001;n= 15) but not forR(–)‐mianserin. The ratio between the AUC(0–12) forS(+)‐mianserin and that forR(–)‐mianserin was higher in poor metabolizers than in extensive metabolizers. Two extremely rapid extensive metabolizer subjects had the lowest mianserinS/Rratios. No differences in the pharmacokinetics of mianserin or desmethylmianserin were found between extensive metabolizers and poor metabolizers ofS‐mephenytoin. The study shows that the elimination of both mianserin and its main metabolite desmethylmianserin is dependent on CYP2D6 activity. Furthermore, the CYP2D6‐dependent elimination of mianserin shows marked enantioselectivity for the more active S(+)‐enantiomer of mianserin.Clinical Pharmacology and Therapeutics(1994)56,

ISSN:0009-9236    

DOI:10.1038/clpt.1994.121

年代:1994

数据来源: WILEY