Suh Jung-Won, Koo Bon-Kwon, Zhang Shu-Ying, Park Kyung-Woo, Cho Joo-Youn, Jang In-Jin, Lee Dong-Soon, Sohn Dae-Won, Lee Myoung-Mook, Kim Hyo-Soo
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
CMAJ. 2006 Jun 6;174(12):1715-22. doi: 10.1503/cmaj.060664.
Clopidogrel is a prodrug requiring metabolism by cytochrome P450 3A (CYP3A) isoenzymes, including CYP3A5, in order to be active. It is controversial whether clopidogrel interacts with CYP3A inhibitors. We investigated the influence of CYP3A5 polymorphism on the drug interaction of clopidogrel.
In phase 1 of the study, we administered clopidogrel to 16 healthy volunteers who had the CYP3A5 non-expressor genotype (*3 allele) and 16 who had the CYP3A5 expressor genotype (*1 allele) with and without pretreatment with itraconazole, a potent CYP3A inhibitor. A platelet aggregation test was performed at baseline, 4 hours, 24 hours and 6 days after clopidogrel administration. In phase 2, we compared clinical outcomes of 348 patients treated with clopidogrel after successful coronary angioplasty with bare-metal stent implantation according to their CYP3A5 genotype; the primary end point was a composite of atherothrombotic events (cardiovascular death, myocardial infarction and non-hemorrhagic stroke) within 1 and 6 months after stent implantation.
In phase 1, the change in platelet aggregation after clopidogrel administration and pretreatment with itraconazole was greater among the subjects with the CYP3A5 expressor genotype than among those with the non-expressor genotype: 24.9% (standard deviation [SD] 13.9%) v. 6.2% (SD 13.5%) at 4 hours (p < 0.001); 27.7% (SD 16.5%) v. 2.5% (SD 8.3%) at 24 hours (p < 0.001); and 33.5% (SD 18.6%) v. 17.8% (SD 13.8%) at day 7 (p < 0.01). In phase 2, atherothrombotic events occurred more frequently within 6 months after stent implantation among the patients with the non-expressor genotype than among those with the expressor genotype (14/193 v. 3/155; p = 0.023). Multivariable analysis showed that the CYP3A5 polymorphism was a predictor of atherothrombotic events in clopidogrel users.
People with the CYP3A5 non-expressor genotype are vulnerable to drug interactions between clopidogrel and CYP3A inhibitors. This phenomenon may be associated with worse outcomes in patients with the non-expressor genotype who are given clopidogrel after coronary angioplasty and implantation of bare-metal stents.
氯吡格雷是一种前体药物，需要通过细胞色素P450 3A（CYP3A）同工酶（包括CYP3A5）进行代谢才能发挥活性。氯吡格雷是否与CYP3A抑制剂相互作用存在争议。我们研究了CYP3A5基因多态性对氯吡格雷药物相互作用的影响。
在研究的第1阶段，我们给16名具有CYP3A5非表达型基因型（*3等位基因）的健康志愿者和16名具有CYP3A5表达型基因型（*1等位基因）的健康志愿者服用氯吡格雷，其中一半志愿者在服用氯吡格雷前接受强效CYP3A抑制剂伊曲康唑预处理。在服用氯吡格雷后的基线、4小时、24小时和6天进行血小板聚集试验。在第2阶段，我们比较了348例接受裸金属支架植入的冠状动脉血管成形术后服用氯吡格雷患者的临床结局，根据他们的CYP3A5基因型分组；主要终点是支架植入后1个月和6个月内的动脉粥样硬化血栓形成事件（心血管死亡、心肌梗死和非出血性卒中）的复合终点。
在第1阶段，服用氯吡格雷并接受伊曲康唑预处理后，CYP3A5表达型基因型受试者的血小板聚集变化大于非表达型基因型受试者：4小时时分别为24.9%（标准差[SD]13.9%）和6.2%（SD 13.5%）（p<0.001）；24小时时分别为27.7%（SD 16.5%）和2.5%（SD 8.3%）（p<0.001）；第7天时分别为33.5%（SD 18.6%）和17.8%（SD 13.8%）（p<0.01）。在第2阶段，支架植入后6个月内，非表达型基因型患者的动脉粥样硬化血栓形成事件发生率高于表达型基因型患者（14/193对3/155；p=0.023）。多变量分析表明，CYP3A5基因多态性是氯吡格雷使用者发生动脉粥样硬化血栓形成事件的预测因素。
具有CYP3A5非表达型基因型的人易发生氯吡格雷与CYP3A抑制剂之间的药物相互作用。这种现象可能与冠状动脉血管成形术和裸金属支架植入后服用氯吡格雷的非表达型基因型患者的较差结局有关。
