Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, South Korea.
J Clin Pharmacol. 2013 May;53(5):550-8. doi: 10.1002/jcph.69. Epub 2013 Feb 4.
In this study, we assessed the effects of clopidogrel and clarithromycin, known CYP2B6 and CYP3A inhibitors, respectively, on the enantioselective disposition of racemic sibutramine in conjunction with CYP2B6 polymorphisms in humans. Sibutramine showed enantioselective plasma profiles with consistently higher concentrations of R-enantiomers. Clopidogrel and clarithromycin significantly increased the sibutramine plasma concentration, but their effects differed between enantiomers; a 2.2-fold versus 4.1-fold increase in the AUC in S-enantiomer and 1.8-fold versus 2.0-fold for the R-enantiomer, respectively. The AUCs of S- and R-desmethyl metabolites changed significantly during the clopidogrel phase (P < .001 and P < .001, respectively) but not during the clarithromycin phase (P = .099 and P = .090, respectively). Exposure to sibutramine was higher in subjects with the CYP2B6*6/*6 genotype, but no statistical difference was observed among the CYP2B6 genotypes. These results suggest that the enantioselective disposition of sibutramine and its active metabolites are influenced by the altered genetic and environmental factors of CYP2B6 and CYP3A activity in vivo.
在这项研究中，我们评估了已知的 CYP2B6 和 CYP3A 抑制剂氯吡格雷和克拉霉素对人类 CYP2B6 多态性与外消旋西布曲明手性药物处置的影响。西布曲明表现出具有一致较高浓度 R-对映体的手性血浆特征。氯吡格雷和克拉霉素显著增加了西布曲明的血浆浓度，但它们对映体的影响不同；S-对映体的 AUC 分别增加了 2.2 倍和 4.1 倍，R-对映体分别增加了 1.8 倍和 2.0 倍。氯吡格雷期 S-和 R-去甲基代谢物的 AUC 发生了显著变化（分别为 P <.001 和 P <.001），但克拉霉素期没有发生变化（分别为 P =.099 和 P =.090）。CYP2B6*6/*6 基因型受试者的西布曲明暴露量更高，但 CYP2B6 基因型之间没有观察到统计学差异。这些结果表明，西布曲明及其活性代谢物的手性药物处置受到 CYP2B6 和 CYP3A 活性体内改变的遗传和环境因素的影响。
