School of Pharmacy, Sungkyunkwan University, Chunchun-dong, Suwon 440-746, Republic of Korea.
J Clin Pharmacol. 2011 Dec;51(12):1704-11. doi: 10.1177/0091270010388651. Epub 2011 Jan 5.
Sibutramine is metabolized by the enzymes CYP2B6 and CYP2C19 into 2 active metabolites, M1 (mono-desmethyl sibutramine) and M2 (di-desmethyl sibutramine). Clopidogrel is a mechanism-based inhibitor of CYP2B6 and CYP2C19. In this study, 13 extensive metabolizers of CYP2B6 and CYP2C19 were evaluated to clarify whether clopidogrel inhibits the formation of the active metabolites of sibutramine. In the control phase, each subject received a 15-mg oral dose of sibutramine. After a washout period of 2 weeks, in the clopidogrel phase, the subjects received 300 mg of clopidogrel on the first day and then 75-mg once daily for 6 days. One hour after the last dosing of clopidogrel, all subjects received 15-mg of sibutramine. Compared with the control phase, the mean sibutramine and M1 plasma concentrations were higher after clopidogrel treatment. Clopidogrel significantly increased the half-life (242% of control phase) and area under the plasma concentration-time curve from 0 to infinity (AUC(inf)) (227% of control phase) of sibutramine and decreased the apparent oral clearance (31% of control phase) of sibutramine. Pharmacokinetic analysis showed significant increases in the AUC(inf) (162% of control phase) of M1. The CYP2B6 and CYP2C19 inhibitor clopidogrel significantly inhibited the formations of M1 from sibutramine and M2 from sibutramine by 37% and 64%, respectively. Therefore, CYP2B6 and CYP2C19 are in vivo catalysts for the formation of the 2 active metabolites of sibutramine.
西布曲明通过 CYP2B6 和 CYP2C19 酶代谢为 2 种活性代谢物，M1（单去甲基西布曲明）和 M2（双去甲基西布曲明）。氯吡格雷是 CYP2B6 和 CYP2C19 的一种基于机制的抑制剂。在这项研究中，评估了 13 名 CYP2B6 和 CYP2C19 的广泛代谢者，以明确氯吡格雷是否抑制西布曲明的活性代谢物的形成。在对照阶段，每个受试者接受 15mg 口服西布曲明剂量。在 2 周洗脱期后，在氯吡格雷阶段，受试者第一天服用 300mg 氯吡格雷，然后每天服用 75mg，连续 6 天。在最后一次氯吡格雷给药后 1 小时，所有受试者均接受 15mg 西布曲明。与对照阶段相比，氯吡格雷治疗后西布曲明和 M1 血浆浓度的平均值更高。氯吡格雷显著增加了西布曲明的半衰期（对照阶段的 242%）和从 0 到无穷大的血浆浓度-时间曲线下面积（AUC（inf））（对照阶段的 227%），并降低了西布曲明的表观口服清除率（对照阶段的 31%）。药代动力学分析显示 M1 的 AUC（inf）显著增加（对照阶段的 162%）。CYP2B6 和 CYP2C19 抑制剂氯吡格雷分别显著抑制 M1 从西布曲明和 M2 从西布曲明的形成 37%和 64%。因此，CYP2B6 和 CYP2C19 是西布曲明的 2 种活性代谢物形成的体内催化剂。
