aDivision of Cardiology, Azienda Ospedaliero-Universitaria of Parma, Italy bDirector, Cardiovascular Genetics Unit, Department of Cardiology, Azienda Ospedaliera Ospedale Niguarda Cà Granda, Milan, Italy.
J Cardiovasc Med (Hagerstown). 2013 Dec;14 Suppl 1:S1-7. doi: 10.2459/JCM.0b013e328364bb04.
The antiplatelet drug clopidogrel is a commonly prescribed therapy in patients with acute coronary syndrome. However, its clinical efficacy is hampered by a wide inter-patient response variability, with over 30% of patients treated with this drug experiencing an inadequate antiplatelet response. There are growing evidences that clopidogrel response variability is associated with cytochrome P450 (CYP) enzyme genetic polymorphisms, primarily CYP2C19 which is responsible for the conversion of clopidogrel into its active metabolite. All of the CYP2C19 polymorphism data suggest that carriers of allele *2 or *17 are at greater risk of ischemic or bleeding events, particularly in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Yet, CYP2C19 status explains only 12% of clopidogrel response variability, indicating that genetic variants other than CYP2C19 might be important. Clopidogrel undergoes intestinal efflux via P-glycoprotein, encoded by the ABCB1 gene. The C3435T polymorphism in this gene affects the bioavailability of clopidogrel, however, its effects on clinical outcomes are inconclusive. Similarly, a polymorphism in the gene encoding PON1, a rate-limiting enzyme for clopidogrel bioactivation, also affects the response to clopidogrel. Among nongenetic factors, an adverse drug interaction between proton pump inhibitors and clopidogrel is often reported, but evidence is inconclusive. A genetic test to identify potential responders to clopidogrel might be useful. However, the use of such tests is currently limited because they focus mainly on CYP2C19 loss-of-function alleles, and there is no empirical evidence yet for genotype-guided clopidogrel therapy.
抗血小板药物氯吡格雷是急性冠状动脉综合征患者的常用治疗药物。然而，其临床疗效受到患者间反应变异性大的限制，超过 30%接受该药物治疗的患者出现抗血小板反应不足。越来越多的证据表明，氯吡格雷反应变异性与细胞色素 P450（CYP）酶遗传多态性有关，主要是 CYP2C19，它负责将氯吡格雷转化为其活性代谢物。所有 CYP2C19 多态性数据表明，携带等位基因 *2 或 *17 的患者发生缺血或出血事件的风险更高，特别是在接受经皮冠状动脉介入治疗的急性冠状动脉综合征患者中。然而，CYP2C19 状态仅解释了 12%的氯吡格雷反应变异性，表明除 CYP2C19 以外的遗传变异可能很重要。氯吡格雷通过 P-糖蛋白（由 ABCB1 基因编码）进行肠外排。该基因中的 C3435T 多态性影响氯吡格雷的生物利用度，但其对临床结局的影响尚无定论。同样，编码氯吡格雷生物活化限速酶 PON1 的基因中的一个多态性也会影响氯吡格雷的反应。在非遗传因素中，质子泵抑制剂与氯吡格雷之间的不良药物相互作用经常被报道，但证据尚无定论。识别氯吡格雷潜在反应者的基因检测可能有用。然而，此类检测的使用目前受到限制，因为它们主要集中在 CYP2C19 功能丧失等位基因上，并且尚未有针对基因型指导的氯吡格雷治疗的经验证据。
