Institute of Geriatric Cardiology, General Hospital of People's Liberation Army, Beijing, China.
Thromb Res. 2011 Oct;128(4):307-16. doi: 10.1016/j.thromres.2011.04.010. Epub 2011 May 18.
Clopidogrel has become the mainstay oral antiplatelet regimen to prevent recurrent ischemic events after acute coronary syndromes or stent placement. However, there is marked interindividual variability in the antiplatelet effects of clopidogrel, and a reduced response to this drug may be a risk factor for ischemic complications. Pharmacogenomic analyses, including candidate-gene and genome-wide association studies, have confirmed that genetic polymorphisms in the hepatic cytochrome P450 (CYP) 2C19 dominantly affect the antiplatelet effects of clopidogrel. CYP2C19 reduced-function alleles have been associated with a significant decrease in clopidogrel responsiveness and a higher risk of adverse cardiac events including stent thrombosis, myocardial infarction, and death in several prospective studies, although these effects were not reproduced in a recent large randomized study that included a randomized control group. The US Food and Drug Administration addressed this issue by adding a boxed warning to the clopidogrel label and suggesting that adjusting the clopidogrel dose or using alternative antiplatelet agents should be potentially implemented for high-risk individuals who are identified based on the CYP2C19 genotype. Although it is promising that CYP2C19 genotyping could be used to guide personalized antiplatelet clopidogrel therapy, currently there is insufficient evidence to recommend routine genetic testing. Prospective randomized clinical trials are necessary to validate this pharmacogenomic approach to clopidogrel therapy. In the most recent trial, paraoxonase-1 (PON1) was identified as a crucial new enzyme for clopidogrel bioactivation, with its common Q192R polymorphism determining the rate of active metabolite and the clinical activity of clopidogrel. Further studies are needed to investigate the comprehensive influence of a number of different polymorphisms of CYP2C19 and PON1 variant alleles or other genetic variants on clopidogrel in various ethnic populations.
氯吡格雷已成为急性冠脉综合征或支架置入后预防复发性缺血事件的主要口服抗血小板药物。然而，氯吡格雷的抗血小板作用存在明显的个体间差异，对该药反应降低可能是缺血并发症的一个危险因素。药物基因组学分析，包括候选基因和全基因组关联研究，已经证实肝细胞色素 P450（CYP）2C19 的遗传多态性显著影响氯吡格雷的抗血小板作用。CYP2C19 功能降低等位基因与氯吡格雷反应性显著降低以及包括支架血栓形成、心肌梗死和死亡在内的不良心脏事件风险增加相关，在几项前瞻性研究中均有报道，尽管在最近一项包括随机对照分组的大型随机研究中未重现这些作用。美国食品和药物管理局（FDA）通过在氯吡格雷标签上添加黑框警告来解决这个问题，并建议对于根据 CYP2C19 基因型确定的高危人群，可能需要调整氯吡格雷剂量或使用替代抗血小板药物。虽然 CYP2C19 基因分型可能用于指导个体化抗血小板氯吡格雷治疗是有希望的，但目前尚无足够证据推荐常规进行基因检测。需要前瞻性随机临床试验来验证这种针对氯吡格雷治疗的药物基因组学方法。在最近的一项试验中，发现对氧磷酶-1（PON1）是氯吡格雷生物活化的一个关键新酶，其常见的 Q192R 多态性决定了活性代谢物的速率和氯吡格雷的临床活性。需要进一步研究来研究 CYP2C19 和 PON1 变异等位基因或其他遗传变异的多个不同多态性对不同种族人群中氯吡格雷的综合影响。
