Polymorphisms of genes related to phase-I metabolic enzymes affecting the clinical efficacy and safety of clopidogrel treatment

Introduction: Clopidogrel is an antiplatelet medication described as a prodrug, which cannot exert the antiplatelet effect until being biotransformed to the active metabolite. It is commonly used to reduce the risk of blood coagulation in patients diagnosed with acute coronary syndrome, or ischemic stroke.Area covered: We reviewed published articles in PubMed and Google Scholar that focused on the mutations of CYP2C19, CYP3A4, CYP2C9, CYP2B6, and CYP1A2 genes related to clopidogrel clinical efficacy and safety.Expert opinion: Based on current pharmacogenetic studies, patients carrying CYP2C19*2, CYP2C19*3, CYP2C9*3, and CYP2B6*5 alleles may not respond to clopidogrel due to poor platelet inhibition efficacy revealed among them. In contrast, carriers of CYP2C19*17, CYP3A4*1G, and CYP1A2*1C alleles showed a more significant antiplatelet effect in clopidogrel users and expected to have a protective role as a genetic factor against cardiovascular events. Genotyping for either CYP2C19, CYP3A4, CYP2C9, CYP2B6, or CYP1A2 variants is not recommended when considering clopidogrel treatment for patients, as some trials showed specific non-genetic factors (e.g. age and diabetes) that could affect clopidogrel responsiveness. Instead, platelets inhibition tests could be used as predictors of the clinical efficacy of clopidogrel treatment. Other P2Y12 receptor inhibitors should be considered as alternative medications.