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.


Related Articles

  • Drug and Medical Device Interactions: Stent Thrombosis and Personalizing Clopidogrel Therapy. Giusti, Betti; Gori, Anna Maria; Marcucci, Rossella; Saracini, Claudia; Vestrini, Anna; Abbate, Rosanna // Current Pharmacogenomics & Personalized Medicine;2010, Vol. 8 Issue 2, p124 

    Antiplatelet therapy with aspirin and clopidogrel, aimed to inhibit platelet function and reactivity, is the recommended standard of care for reducing the occurrence of cardiovascular events in patients with acute coronary syndromes undergoing percutaneous coronary intervention with stent...

  • Clopidogrel.  // Reactions Weekly;1/21/2006, Issue 1085, p11 

    This article presents a case report of a male patient who developed acute polyarthritis during treatment with clopidogrel for coronary artery disease. It provides a background on the medical history of the patient. It offers information on the medication administered to the patient for acute...

  • The Effect of Cytochrome P450 Metabolism on Drug Response, Interactions, and Adverse Effects. Lynch, Tom; Price, Amy // American Family Physician;8/1/2007, Vol. 76 Issue 3, p391 

    Cytochrome P450 enzymes are essential for the metabolism of many medications. Although this class has more than 50 enzymes, six of them metabolize 90 percent of drugs, with the two most significant enzymes being CYP3A4 and CYP2D6. Genetic variability (polymorphism) in these enzymes may influence...

  • Interethnic Differences in Genetic Polymorphisms of CYP2D6 in the U.S. Population: Clinical Implications. Stephen Bernard // Oncologist;Feb2006, Vol. 11 Issue 2, p126 

    DNA polymorphisms have been identified in the genes encoding a number of the cytochrome P450 (CYP) enzymes, leading to wide interindividual variation in drug clearance. CYP2D6 metabolizes a significant number of clinically used medications, and genetic variants of the CYP2D6 isozyme that result...

  • Paclitaxel/sirolimus.  // Reactions Weekly;6/13/2009, Issue 1256, p27 

    The article describes the case of three patients who developed very late drug-eluting stent thromboses after placement of paclitaxel- or sirolimus-eluting stents. A man was diagnosed with coronary artery disease involving the right coronary artery (RCA), several years after undergoing...

  • PPIs and clopidogrel. Elliott, William T. // Travel Medicine Advisor;May2009 Supplement, p2 

    The article discusses a cohort study on proton pump inhibitors (PPIs) and clopidogrel. According to the study involving 8205 patients with acute coronary syndrome (ACS), patients who take PPIs and clopidogrel are at a higher risk of experiencing adverse outcomes. It concluded that PPIs may...

  • Drug Interactions of Lipid-Altering Drugs. Bays, H.E.; Dujovne, C.A. // Drug Safety;Nov1998, Vol. 19 Issue 5, p355 

    The use of lipid-altering drugs has been shown to reduce the progression of atherosclerotic lesions and reduce the risk of atherosclerotic events (such as myocardial infarction and stroke). In general, these lipid-altering drugs are well tolerated but there is the potential for drug...

  • eptifibatide.  // Davis's Drug Guide for Nurses, 10th edition;2007, p465 

    The article presents a nursing guide to eptifibatide, an antiplatelet agent used to treat acute coronary syndrome. Indications and contraindications are mentioned. Adverse reactions to the drug are cited, including hypotension and bleeding. Nursing implications and desired outcomes are provided....

  • Immune globulin.  // Reactions Weekly;2/11/2006, Issue 1088, p15 

    This article presents a case report involving a male patient who experienced a myocardial infarction during treatment with immune globulin for toxic epidermal necrolysis secondary to allopurinol exposure. It provides a background on the medical history of the patient. It describes the symptoms...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics