Effects of Omeprazole and Genetic Polymorphism of CYP2C19 on the Clopidogrel Active Metabolite
Effects of Omeprazole and Genetic Polymorphism of CYP2C19 on the Clopidogrel Active Metabolite
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DOI：
10.1124/dmd.111.040394
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发表时间：
2012-01-01
影响因子：
3.9
通讯作者：
Hurbin, Fabrice
中科院分区：
文献类型：
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作者：
Boulenc, Xavier;Djebli, Nassim;Hurbin, Fabrice
氯吡格雷是一种广泛用于心血管疾病的抗血小板药物，也是一种非活性前药，需要通过两个连续的代谢步骤转化为活性代谢物。在这两个步骤中涉及的几种CYP450亚型已经被描述，尽管每种酶在体内的相对贡献仍然存在争议。CYP2C19被认为是活性代谢物形成的主要贡献者。在目前的研究中，CYP2C19对活性代谢物形成的净贡献是通过两项临床研究（一项具有良好平衡的遗传多态性群体的I期研究和一项共有396名健康志愿者的荟萃分析）在不同氯吡格雷剂量下暴露于活性代谢物来确定的。根据研究和剂量的不同，CYP2C19在中间代谢物（IMs）中参与的比例为58%至67%，在广泛代谢物（EMs）中参与的比例为58%至72%，在超快速代谢物（UMs）中参与的比例为56%至74%。为此，提出了一个静态模型来估计给定酶对次生代谢物形成的净贡献。将该静态模型与动态方法（Simcyp模型）进行比较，结果显示出较好的一致性。同时，体外研究表明，奥美拉唑是一种基于机制的CYP2C19抑制剂，K-I为8.56 μ M， K-inact为0.156 min（-1）。这些值与CYP2C19对活性代谢物形成的净贡献相结合，通过静态方法预测80 mg奥美拉唑剂量对EM， IM和UM CYP2C19人群的抑制作用，与观察到的临床值相比具有良好的一致性。
Clopidogrel is an antiplatelet agent widely used in cardiovascular diseases and an inactive prodrug that needs to be converted to an active metabolite in two sequential metabolic steps. Several CYP450 isoforms involved in these two steps have been described, although the relative contribution in vivo of each enzyme is still under debate. CYP2C19 is considered to be the major contributor to active metabolite formation. In the current study, net CYP2C19 contribution to the active metabolite formation was determined from exposure of the active metabolite in two clinical studies (one phase I study with well balanced genetic polymorphic populations and a meta-analysis with a total of 396 healthy volunteers) at different clopidogrel doses. CYP2C19 involvements were estimated to be from 58 to 67% in intermediate metabolizers (IMs), from 58 to 72% in extensive metabolizers (EMs), and from 56 to 74% in ultrarapid metabolizers (UMs), depending on the study and the dose. For this purpose, a static model was proposed to estimate the net contribution of a given enzyme to the secondary metabolite formation. This static model was compared with a dynamic approach (Simcyp model) and showed good consistency. In parallel, in vitro investigations showed that omeprazole is a mechanism-based inhibitor of CYP2C19 with K-I of 8.56 mu M and K-inact of 0.156 min(-1). These values were combined with the net CYP2C19 contribution to the active metabolite formation, through a static approach, to predict the inhibitory effect at 80-mg omeprazole doses in EM, IM, and UM CYP2C19 populations, with good consistency, compared with observed clinical values.