代谢物在预测药物相互作用中的作用：聚焦于不可逆细胞色素P450抑制作用
The role of metabolites in predicting drug-drug interactions: focus on irreversible cytochrome P450 inhibition.
作者信息
VandenBrink Brooke M, Isoherranen Nina
机构信息
University of Washington, Department of Medicinal Chemistry, Box 357610, Seattle, WA 98195, USA.
出版信息
Curr Opin Drug Discov Devel. 2010 Jan;13(1):66-77.
Abstract
The irreversible inhibition of cytochrome P450 (CYP) enzymes can cause significant drug-drug interactions (DDIs). The formation of metabolites is fundamental for the inactivation of CYP enzymes. Of the 19 CYP enzyme inactivators for which the mechanism of action has been established, 10 have circulating metabolites, which are on the metabolic pathway to inactivation of the CYP enzyme. Because inactivation of CYP enzymes usually requires multiple metabolic steps, the prediction of interactions between metabolites and CYPs in vivo may require complex models and the availability of data generated in vitro from each metabolite. Data discussed in this review suggest that circulating metabolites are more important in CYP inhibition in vivo than has been acknowledged.
摘要
细胞色素P450（CYP）酶的不可逆抑制可导致显著的药物-药物相互作用（DDIs）。代谢物的形成是CYP酶失活的基础。在已确定作用机制的19种CYP酶失活剂中，有10种具有循环代谢物，这些代谢物处于CYP酶失活的代谢途径上。由于CYP酶的失活通常需要多个代谢步骤，因此预测体内代谢物与CYPs之间的相互作用可能需要复杂的模型以及每种代谢物体外生成数据的可用性。本综述中讨论的数据表明，循环代谢物在体内CYP抑制中比以往所认识到的更为重要。
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