Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel

Jung-Won Suh; Bon-Kwon Koo; Shu-Ying Zhang; Kyung-Woo Park; Joo-Youn Cho; In-Jin Jang; Dong-Soon Lee; Dae-Won Sohn; Myoung-Mook Lee; Hyo-Soo Kim
June 2006
CMAJ: Canadian Medical Association Journal;6/6/2006, Vol. 174 Issue 12, p1715
Academic Journal
Background: 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 CYP3A5polymorphism on the drug interaction of clopidogrel. Methods: In phase 1 of the study, we administered clopidogrel to 16 healthy volunteers who had the CYP3A5 nonexpressor 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. Results: In phase 1, the change in platelet aggregation after clopidogrel administration and pretreatment with itraconazole was greater among the subjects with the CYP3A5expressor 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 CYP3A5polymorphism was a predictor of atherothrombotic events in clopidogrel users.


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