摘要:

Aminopyrine and caffeine metabolism was evaluated in vivo in 21 healthy volunteers in order to elucidate whether the acetylation capacity of the two substances correlates. The ratio of the aminopyrine metabolites 4-acetyl-aminoantipyrine (AAA)/4-aminoantipyrine (AA) was compared with the ratios of caffeine metabolites AAMU/1-X and AAMU/(AAMU + 1-X + 1-U). All the subjects phenotyped as slow acetylators with caffeine displayed AAA/AA ratios lower than 3.4, whereas the extensive acetylators had ratios higher than 3.8. Therefore, the acetylator phenotype determined with caffeine cosegre-gated with the capacity to acetylate the aminopyrine metabolite AA. The N-demethylation of aminopyrine and caffeine correlated strongly in the subjects studied (p < 0.001). A highly significant correlation (r = 0.92; p < 0.001) was also observed between caffeine N(l)- and N(7)-demethylation activities. In addition, most N-demethylation steps of both drugs significantly correlated, suggesting partial contributions by identical or closely related enzymes in their metabolism.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Pharmacokinetics of valproic acid sustained-release preparation (VPA-SR) were studied in nine patients undergoing surgery for brain tumor. Total (t) and free (f) serum concentrations were analyzed in samples drawn during the day of brain surgery and compared with levels from a postoperative day. The area under the curve (AUCt) and clearance (CLt) of the total concentration did not differ on these occasions. In contrast, statistically significant differences were observed in AUCfand CLfbetween the two occasions; increased AUCfand decreased CLfwere observed on the day of surgery. A significant relation was found between the average free fraction (AUCf/AUCton operation day per AUCf/AUCton postoperative day) and estimated blood loss during operation (r = 0.82; p < 0.001). In addition, a significant relation was found between simple free fraction and the intraoperative albumin level in serum (r = −0.68; p < 0.001). These findings indicate that the increased VPA free concentration is due to low serum albumin level secondary to blood loss and that there has been a decrease in intrinsic clearance during operation.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

A systematic approach to individualizing the phenytoin (PHT) dose from a previous dose (D) and steady-state concentration (Css) pair was established by the combined use of two methods based on recently reported population pharmacokinetic parameters. This system applies the Michaelis-Menten equation to the initial data pair (D1-Css1) and solves for (a) maximum metabolic rate constant (Vmax) assuming the population mean for the Michaelis constant (Km) (method 1), and (b) Kmassuming the population mean for Vmax(method 2). The derived estimates of Vmaxand Kmare then put through a series of filters, which results in the selection of method 1 and/or method 2 or allocation of a third category that needs further evaluation. A simulation study was performed to find a series of filters. The presented approach was applied retrospectively to the patients' data of 35 sets. Accurate predictions of the Csserror within 5 μg/ml were obtained in 84% of the 25 cases, and in 30% of the 10 cases excluded. This systematic approach gives better prediction performance in mean error, mean absolute error, and root mean square error than a Bayesian feedback method.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

The presence of digitoxin-like immunoreactive substances, whose nature is yet unknown, has been demonstrated in the umbilical cord blood. We selected six antidigitoxin monoclonal antibodies (MAb) having different specificity profiles concerning digitoxin analogs and steroid hormones. These antibodies were tested in a digitoxin radioimmunoassay (RIA). With the help of this technique, we measured the concentrations of apparent digitoxin in the cord blood drawn either at birth or in utero from mothers not undergoing any digitalis treatment. In the cord blood of newborns, the concentrations of apparent digitoxin, measured by the two MAbs that have the highest cross-reactions with dehydroepiandrosterone (DHEA) (123A23 and 145A41), were two or three times higher than with the other antibodies. In the fetal cord blood, where the concentration of DHEA is five to seven times lower than that observed at birth, these antibodies revealed a threefold lower concentration of apparent digitoxin than that observed in blood drawn at birth. Furthermore, MAbs that had similar specificities towards digitoxin analogs and steroids showed different measurements of digitoxin-like concentrations. These observations suggest that digitoxin-like immunoreactive compounds detected by the RIA may constitute a group of different molecules, one of which would be the DHEA.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Total and ultrafilterable platinum (Pt) disposition was investigated during 49 courses of chemotherapy in 13 patients with germ cell tumor treated with cisplatin (DDP), 20 mg/m2/day on 5 consecutive days. The following pharmacokinetic parameters were analyzed: distribution (t1/2α) and elimination (t1/2β) half-lives, total body clearance (ClT), renal clearance (ClR), and areas under the concentration versus time curve (AUCs). Blood samples were collected immediately before and after DDP infusion (Day 1 through Day 5); in addition, on Day 5, samples were collected at 0.25, 0.5, 1, 8, 24, and 48 h after DDP infusion. Urine was collected during each day of treatment and up to 48 h after the last DDP dose. During each chemotherapy cycle plasma levels of total and ultrafilterable Pt progressively increased from the first to the last day of treatment. At the first cycle, total Pt concentrations ranged from 0.67 to 1.46 μg/ml (mean increase, 118%), and those of ultrafilterable Pt from 0.117 to 0.205 μg/ml (mean increase, 75%). Mean ± SD total Pt plasma levels immediately postinfusion increased from 0.67 ± 0.20 μg/ml at the first cycle (first day of therapy) to 1.13 ± 0.21 μg/ml at the same time point at the fourth cycle. Mean total Pt peak levels were reached at the end of infusion on the last day of each cycle, and increased from 1.46 ± 0.29 μg/ml (first cycle) to 1.89 ± 0.40 μg/ml (fourth cycle). Total Pt was detectable in plasma before the beginning of all cycles following the first. As a result, AUC significantly increased and ClRsignificantly decreased. However, this change was no longer evident when calculations were made taking into account the pretreatment values of total Pt. Plasma concentrations of ultrafilterable Pt did not show any significant change between the first and subsequent cycles; nor was there any significant modification in the pharmacokinetic parameters studied.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Ticlopidine is a novel antiplatelet drug reported to cause significant inhibition of several drugs metabolized by the hepatic cytochrome P-450 enzyme system, including antipyrine and theophylline. Warfarin, a racemic mixture of two enantiomers (R and S), is extensively metabolized by the CYP-450 system. S-Warfarin is five to eight times as active as R-warfarin. The effects of ticlopidine on the pharmacokinetics and pharmacodynamics of warfarin were examined in nine elderly men (69 ± 4 years) receiving long-term warfarin therapy. Steady-state warfarin enantiomer concentrations and International Normalized Ratios (INRs) were determined at baseline and after 14 days of treatment with oral ticlopidine, 250 mg twice daily. Warfarin enantiomer serum concentrations were determined by high-performance liquid chromatography after chiral derivitization. Ticlopidine co-medication resulted in a significant increase in mean R-warfarin concentrations ( + 25.7%, p < 0.05), while no significant difference in S-warfarin concentrations was noted ( +0.8%). Mean INR values were not significantly different from the baseline ( +8.3%), although substantial interindividual variability was noted. We conclude that ticlopidine co-medication does result in an enantioselective kinetic interaction with warfarin; however, this interaction is likely to be of minimal clinical significance in most patients.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

The pharmacokinetic variability of moclobemide, a new short half-life reversible selective inhibitor of monoamine oxidase (MAO) was investigated through analysis of concentrations measured during early open clinical use. Eighty-nine depressed patients, aged 21–96 years, were included in the present study. Doses ranged from 200 to 900 mg/day, and the time interval between blood sampling and last drug intake on the previous day was between 8 and 23 h. Intraindividual variability was generally moderate, with a few patients displaying consistently high concentrations despite moderate doses. Interindividual variability for measured concentrations was ∼300-fold. After concentration decrease with time was taken into account (average half-life estimate of 4.6 h), age was identified as a major factor responsible for between-patient variability. Average concentration increase per decade of age was 38%. Neither gender, weight, height, smoking, nor alcohol intake explained a significant additional part of the variance. Analysis of residuals also suggested that phenytoin co-medication may induce moclobemide metabolism. The present study indicates that concentration monitoring of a newly marketed drug can contribute to gaining insight into its pharmacokinetic behavior and to enhancing its rational use in clinical practice.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Plasma carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-E) concentrations were measured in 160 epileptic patients in order to determine the effect of factors such as age, daily dosing schedule, formulation, and combination with other antiepileptic drugs on these concentrations in relation to the daily dose. The results showed that the CBZ plasma level/dose ratio was affected by all factors studied, whereas the CBZ-E plasma level/dose ratio was affected only by formulation and age. The ratio of CBZ-E to CBZ plasma levels (CBZ-E/CBZ) was affected by daily dosing schedule, age, and combination with other antiepileptic drugs. The present study demonstrated that many factors affect plasma CBZ/dose ratios, explaining the discrepancies observed in the literature.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Pretreatment of human serum with 5-sulfosalicylic acid (SSA) as used in the Abbott TDx digoxin assay produces deglycosylated congeners of digoxin (DIG) and of endogenous digoxin-like immunoreactive factor (DLIF). Using high-performance liquid chromatography analysis, we observed differences in the degree and pattern of DIG breakdown products among five patients. The aglycone digoxigenin was the major product in several samples. Smaller amounts of the bis- and mono-digitoxosides and unidentified products less polar than DIG were sometimes present. Treatment of DLIF-containing plasma with SSA produced similar patterns of DLIF-breakdown products. Incubation of normal plasma containing DIG with SSA for up to 30 min caused little change in measured DIG by TDx and radioimmunoassay (RIA) but decreased to 50% in the ACS DIG assay. These results are consistent with the near 100% cross-reactivities of deglycosylated DIG congeners in the TDx and RIA assays compared to their lower cross-reactivities in the ACS assay. We conclude that the breakdown of DIG and DLIF during treatment of serum with SSA may compromise the accuracy of TDx DIG assays and may explain discrepancies observed in other studies between digoxin immunoassays. This study underscores the importance of understanding the effects of pretreatment strategies used for analytes measured by immunoassay.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Verapamil and norverapamil trough plasma levels were measured in 22 children, aged from 15 days to 17 years, under chronic oral treatment with the drug (mean daily dose ± SD: 4.9 ± 1.4 mg/kg) for supraventricular tach-yarrhythmias (n = 20) or hypertrophic cardiomyopathy (n = 2). Overall, 67 determinations were available (1 to 11 per patient) and the mean concentration values (± SD) were 43.3 ± 36.4 ng/ml for verapamil and 41.7 ± 28.9 ng/ml for norverapamil. Verapamil and norverapamil trough concentrations were correlated with the daily dose (p < 0.05) but a wide intersubject variability was present at any given dose and the regression line did not pass through the origin of axes (x-axis intercept: 1.2 mg/kg for verapamil, 0.9 mg/kg for norverapamil). To study the influence of age on drug kinetics, verapamil plasma concentrations corrected by daily dose/kg ([V]/D) and norverapamil to verapamil concentration ratios (N/V) (taken as an index of metabolic clearance) were divided according to age quartiles. The median [V]/D was higher in the first and in the fourth age quartile than in the other two age groups. On the contrary, median N/V ratio increased with age, suggesting that drug metabolism was improving during the first year of life. Four children developed typical adverse reactions to the drug (bradycardia, AV block, hypotension). In one case verapamil plasma levels were definitely high (294 ng/ml). In the other three cases, concomitant factors (such as very young age and heart disease) seem to have contributed to drug toxicity.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID