考来烯胺的同时给药会影响曲格列酮的吸收。

Concomitant administration of cholestyramine influences the absorption of troglitazone.

作者信息

Young M A, Lettis S, Eastmond R

机构信息

Department of Clinical Pharmacokinetics and Dynamics, Glaxo Wellcome Research and Development Ltd, Greenford, Middlesex, UK.

出版信息

Br J Clin Pharmacol. 1998 Jan;45(1):37-40. doi: 10.1046/j.1365-2125.1998.00645.x.

DOI:10.1046/j.1365-2125.1998.00645.x

PMID:9489592

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1873999/

Abstract

AIM

Troglitazone is an orally active anti-diabetic agent. Cholestyramine is an orally administered lipid-lowering agent which acts by binding to bile acids and removing them from enterohepatic circulation. Preclinical studies suggesting the potential for an interaction between troglitazone and cholestyramine require confirmation in a clinical setting.

METHODS

In vitro and in vivo experiments in the dog were carried out prior to a clinical study. Twelve healthy volunteers (mean age 32 years, range 20-44 years) each received a single oral dose of troglitazone 400 mg alone and with cholestyramine 12 g (taken 1 h after troglitazone) in an open, two-way crossover study.

RESULTS

In vitro, about 99% of troglitazone was adsorbed by cholestyramine at an incubate concentration of 3 microg ml(-1) whilst at 500 microg ml(-1) adsorption fell to about 90%. In vivo, AUC of troglitazone was reduced by an average of 42% (22.7 vs 12.2 microg ml(-1) h (95% CI for difference 28-57, P=0.01) in 11 beagle dogs receiving troglitazone 200 mg and cholestyramine 1 g compared with control values. Mean maximum plasma concentration (Cmax) was 49% of control values (7.08 vs 3.42 microg ml(-1) (95% CI for difference 14-85, P=0.05)). In the clinical study median AUC for troglitazone and its two major metabolites were statistically significantly lower when troglitazone was administered with cholestyramine (17.9 vs 5.2 microg ml(-1) h (95% CI for difference -20.5, -8.7), 133.7 vs 27 1 microg ml(-1) h (-166.4, -67.8) and 18.4 vs 2.5 microg ml(-1) h (-21.6, -10.6) for troglitazone, sulphate and quinone metabolite respectively (all P < 0.01) representing percentage decreases of 71, 80 and 86% respectively. A statistically significant reduction was also observed in Cmax for the sulphate metabolite (4.56 vs 1.28 microg ml(-1) (95% CI for difference -4.42, -1.99, P < 0.01)), but not for troglitazone (1.85 vs 1.23 microg ml(-1) (-1.13, 0.49) or the oxidative metabolite (0.84 vs 0.45 microg ml(-1) (-0.77, 0.09)).

CONCLUSIONS

The results were indicative of an alteration in the extent of troglitazone's absorption. Concomitant administration of troglitazone and cholestyramine could severely impair troglitazone's clinical utility as an antihyperglycaemic agent.

摘要

目的

曲格列酮是一种口服有效的抗糖尿病药物。考来烯胺是一种口服降脂药物，通过与胆汁酸结合并将其从肠肝循环中清除而起作用。临床前研究提示曲格列酮与考来烯胺之间可能存在相互作用，这需要在临床环境中得到证实。

方法

在一项临床研究之前，先在犬身上进行了体外和体内实验。在一项开放的、双向交叉研究中，12名健康志愿者（平均年龄32岁，范围20 - 44岁）每人分别单独口服400 mg曲格列酮，以及在服用曲格列酮1小时后服用12 g考来烯胺。

结果

在体外，当孵育浓度为3μg/ml⁻¹时，约99%的曲格列酮被考来烯胺吸附，而当浓度为500μg/ml⁻¹时，吸附率降至约90%。在体内，与对照组相比，11只接受200 mg曲格列酮和1 g考来烯胺的比格犬中，曲格列酮的AUC平均降低了42%（22.7对12.2μg/ml⁻¹·h（差异的95%置信区间为28 - 57，P = 0.01））。平均最大血浆浓度（Cmax）为对照值的49%（7.08对3.42μg/ml⁻¹（差异的95%置信区间为14 - 85，P = 0.05））。在临床研究中，当曲格列酮与考来烯胺合用时，曲格列酮及其两种主要代谢物的中位AUC在统计学上显著降低（曲格列酮、硫酸盐和醌代谢物分别为17.9对5.2μg/ml⁻¹·h（差异的95%置信区间为 - 20.5， - 8.7），133.7对27.1μg/ml⁻¹·h（ - 166.4， - 67.8）和18.4对2.5μg/ml⁻¹·h（ - 21.6， - 10.6）（所有P < 0.01），分别代表降低了71%、80%和86%）。硫酸盐代谢物的Cmax也有统计学上的显著降低（4.56对1.28μg/ml⁻¹（差异的95%置信区间为 - 4.42， - 1.99，P < 0.01）），但曲格列酮（1.85对1.23μg/ml⁻¹（ - 1.13，0.49））或氧化代谢物（0.84对0.45μg/ml⁻¹（ - 0.77，0.09））没有。