Advertisement
ADVANCED SEARCH

This Article Figures Only Full Text Full Text (PDF) Online Appendix Correction (v175,p64) Submit a response View responses Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Suh, J.-W. Articles by Kim, H.-S. Search for Related Content PubMed PubMed Citation Articles by Suh, J.-W. Articles by Kim, H.-S. Related Collections Drugs: cardiovascular system Adverse drug reactions Genetics Related Article

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

From the Departments of Internal Medicine (Suh, Koo, Park, Sohn, Kim), Pharmacology (Cho, Jang) and Laboratory Medicine (Dong-Soon Lee), Seoul National University College of Medicine, Seoul, Korea; the Cardiovascular Center (Myoung-Mook Lee), Dong-Kook University Ilsan Hospital, Kyungki-do, Korea; and the Cardiovascular Laboratory (Kim), Clinical Research Institute, Seoul National University Hospital, Seoul, Korea

Correspondence to: Dr. Hyo-Soo Kim, Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul, 110-744, Korea; fax 82-2-766-8904; hyosoo{at}snu.ac.kr

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.

This article has been cited by other articles:

				C. Verstuyft, T. Simon, and R. B. Kim Personalized medicine and antiplatelet therapy: ready for prime time? Eur. Heart J., August 2, 2009; 30(16): 1943 - 1963. [Full Text] [PDF]

				N. F. Ford Clopidogrel Resistance: Pharmacokinetic or Pharmacogenetic? J. Clin. Pharmacol., May 1, 2009; 49(5): 506 - 512. [Abstract] [Full Text] [PDF]

				T. Simon, C. Verstuyft, M. Mary-Krause, L. Quteineh, E. Drouet, N. Meneveau, P. G. Steg, J. Ferrieres, N. Danchin, L. Becquemont, et al. Genetic Determinants of Response to Clopidogrel and Cardiovascular Events N. Engl. J. Med., January 22, 2009; 360(4): 363 - 375. [Abstract] [Full Text] [PDF]

				J. L. Mega, S. L. Close, S. D. Wiviott, L. Shen, R. D. Hockett, J. T. Brandt, J. R. Walker, E. M. Antman, W. Macias, E. Braunwald, et al. Cytochrome P-450 Polymorphisms and Response to Clopidogrel N. Engl. J. Med., January 22, 2009; 360(4): 354 - 362. [Abstract] [Full Text] [PDF]

				P. Gladding, M. Webster, I. Zeng, H. Farrell, J. Stewart, P. Ruygrok, J. Ormiston, S. El-Jack, G. Armstrong, P. Kay, et al. The Pharmacogenetics and Pharmacodynamics of Clopidogrel Response: An Analysis From the PRINC (Plavix Response in Coronary Intervention) Trial J. Am. Coll. Cardiol. Intv., December 1, 2008; 1(6): 620 - 627. [Abstract] [Full Text] [PDF]

				J. M. Siller-Matula, I. Lang, G. Christ, and B. Jilma Calcium-Channel Blockers Reduce the Antiplatelet Effect of Clopidogrel J. Am. Coll. Cardiol., November 4, 2008; 52(19): 1557 - 1563. [Abstract] [Full Text] [PDF]

				L. T. Newsome, R. S. Weller, J. C. Gerancher, M. A. Kutcher, and R. L. Royster Coronary Artery Stents: II. Perioperative Considerations and Management Anesth. Analg., August 1, 2008; 107(2): 570 - 590. [Abstract] [Full Text] [PDF]

				T. Geisler, C. Zurn, M. Paterok, K. Gohring-Frischholz, B. Bigalke, K. Stellos, P. Seizer, B. F. Kraemer, J. Dippon, A. E. May, et al. Statins do not adversely affect post-interventional residual platelet aggregation and outcomes in patients undergoing coronary stenting treated by dual antiplatelet therapy Eur. Heart J., July 1, 2008; 29(13): 1635 - 1643. [Abstract] [Full Text] [PDF]

				S. De Fazio, L. Gallelli, A. De Siena, G. De Sarro, and M. G. Scordo Role of CYP3A5 in Abnormal Clearance of Methadone Ann. Pharmacother., June 1, 2008; 42(6): 893 - 897. [Abstract] [Full Text] [PDF]

				P. A. Gurbel, W. C. Lau, and U. S. Tantry Omeprazole: A Possible New Candidate Influencing the Antiplatelet Effect of Clopidogrel J. Am. Coll. Cardiol., January 22, 2008; 51(3): 261 - 263. [Full Text] [PDF]

				J. B. Dennison, D. R. Jones, J. L. Renbarger, and S. D. Hall Effect of CYP3A5 Expression on Vincristine Metabolism with Human Liver Microsomes J. Pharmacol. Exp. Ther., May 1, 2007; 321(2): 553 - 563. [Abstract] [Full Text] [PDF]

				M. Guirguis Atherothrombotic events and clopidogrel therapy Can. Med. Assoc. J., January 30, 2007; 176(3): 349 - 349. [Full Text] [PDF]

				J.-W. Suh, B.-K. Koo, and H.-S. Kim Atherothrombotic events and clopidogrel therapy Can. Med. Assoc. J., January 30, 2007; 176(3): 351 - 351. [Full Text] [PDF]

				C. S. McLachlan, S. K.H. Tay, Z. Almsherqi, and S.-H. Chia Atherothrombotic events and clopidogrel therapy Can. Med. Assoc. J., January 30, 2007; 176(3): 349 - 349. [Full Text] [PDF]

				M. Tang, M. Mukundan, J. Yang, N. Charpentier, E. L. LeCluyse, C. Black, D. Yang, D. Shi, and B. Yan Antiplatelet Agents Aspirin and Clopidogrel Are Hydrolyzed by Distinct Carboxylesterases, and Clopidogrel Is Transesterificated in the Presence of Ethyl Alcohol J. Pharmacol. Exp. Ther., December 1, 2006; 319(3): 1467 - 1476. [Abstract] [Full Text] [PDF]

				M. O'Donoghue and S. D. Wiviott Clopidogrel Response Variability and Future Therapies: Clopidogrel: Does One Size Fit All? Circulation, November 28, 2006; 114(22): e600 - e606. [Full Text] [PDF]

				Corrections Can. Med. Assoc. J., July 4, 2006; 175(1): 64 - 64. [Full Text] [PDF]

				J. Turgeon, C. Pharand, and V. Michaud Understanding clopidogrel efficacy in the presence of cytochrome P450 polymorphism Can. Med. Assoc. J., June 6, 2006; 174(12): 1729 - 1729. [Full Text] [PDF]

eLetters:

HOME	CURRENT ISSUE	PAST ISSUES	COLLECTIONS	HELP	SEARCH
Copyright 1995-2006, Canadian Medical Association. All rights reserved. ISSN 1488-2329 (e) 0820-3946 (p) All editorial matter in CMAJ represents the opinions of the authors and not necessarily those of the Canadian Medical Association.