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

Cited 166 time in Web of Science Cited 181 time in Scopus
Authors
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
Issue Date
2006-06-06
Publisher
HighWire
Citation
CMAJ 2006;174:1715-22
Keywords
Cytochrome P-450 CYP3ACytochrome P-450 Enzyme System/antagonists &inhibitors/*genetics/metabolismDrug InteractionsEmbolism, Cholesterol/*chemically inducedEnzyme Inhibitors/adverse effectsGenotypePlatelet Aggregation Inhibitors/*adverse effects/metabolism*Polymorphism, GeneticRisk FactorsThrombosis/*chemically inducedTiclopidine/adverse effects/*analogs & derivatives/metabolism
Abstract
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 CYP3A5 polymorphism on the drug interaction of clopidogrel. METHODS: 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. RESULTS: 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. INTERPRETATION: 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.
ISSN
1488-2329 (Electronic)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16754899

http://hdl.handle.net/10371/12119
DOI
https://doi.org/10.1503/cmaj.060664
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College of Medicine/School of Medicine (의과대학/대학원)Laboratory Medicine (검사의학전공)Journal Papers (저널논문_검사의학전공)
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