氯吡格雷药物基因组学研究进展

Advances in pharmaconenomic studies of clopidogrel

氯吡格雷是一种普遍使用的P2Y12血小板抑制剂,它和阿司匹林联合使用是预防和治疗急性冠脉综合征(ACS)以及经皮介入治疗患者的临床标准用药。氯吡格雷是药物前体,需要经过小肠的吸收和肝脏细胞色素P450(CYP)的两步代谢才能转化为有活性的代谢产物(R-130964)。研究表明氯吡格雷活性代谢物的转化主要受细胞色素P4502C19(CYP2C19)基因多态性的影响。CYP2C19失去功能型等位基因(主要是CYP2C19*2,CYP2C19*3)携带者与血浆氯吡格雷活性代谢物浓度以及生物利用度降低、不良心血管事件危险性增加有关。而ABCB1,CYP2B6等其他基因的多态性与氯吡格雷活性代谢物以及不良心血管事件的关系有待于在不同人群中进一步研究。基因检测以及通过选择适当的个性化治疗方案可以帮助携带CYP2C19*2,*3等位基因的患者减少危险,增加氯吡格雷的有效性和安全性。

Dual antiplatelet therapy with a combination of aspirin and clopidogrel, a popular P2Y12 recep- tor antagonist, is a standard therapy for patients with acute coronary syndromes （ACS） and for those treated with percutaneous coronary intervention （PCI）. Clopidogrel is a prodrug that requires a two-step hepatic conversion into an active metabolite（R-130964） to exert its antiplatelet effect. Studies showed that the biotranformation of the ac- tive metabolite of clopidogrel was affected by the polymorphism of CYP2C19. Carriers of CYP2C19 loss-of-function allele （ mainly CYP2C19 ＊ 2, ＊ 3） were associated with decrease of plasma concentration and bioavailability of the active metabolite of clopidogrel as well as increase of cardiovascular event risk. The association between other genes such as ABCB1 and CYP2B6 and clopidogrel active metabolite as well as cardiovascular event risk requires further exploration. Gene detection and personalized medicine can help decrease the risks and increase clopidogrel efficacy and safety in CYP2C19 ＊ 2, ＊ 3 carriers.