Clopidogrel Pharmacogenetics

Abstract

Clopidogrel is a pro-drug that requires oxidation to its active metabolite, 2-oxoclopidogrel, by CYP3A4 and other CYP enzymes. This active thiol metabolite inhibits adenosine diphosphate (ADP)-induced platelet aggregation by blocking the platelet P2Y12 receptor (Figure), resulting in ≈50% reduction in ADP-mediated platelet aggregation. Clopidogrel is standard of care in many patients undergoing percutaneous coronary intervention (PCI) and those experiencing acute coronary syndromes. However, it has been suggested that response to clopidogrel varies widely with nonresponse rates ranging from 4% to 30% at 24 hours.1,2 Suggested mechanisms for this variability have included under-dosing, drug interactions with CYP3A4 substrates and inhibitors,3 and intrinsic interindividual differences resulting from genetic polymorphisms in the pathways of clopidogrel pharmacokinetics and pharmacodynamics. Clopidogrel metabolism and mechanism of action. Clopidogrel is metabolized to its active metabolite by the cytochrome P450 (CYP) 3A enzyme family. The CYP3A gene family is located on chromosome 7q21-q22. Genes are shown as block arrows. Select CYP3A4 and CYP3A5 polymorphisms (named according to the Human CYP Allele Nomenclature Committee) are shown with vertical black lines in relation to their position in the genes. The proposed effect of the polymorphisms on protein expression or function is shown below. CYP3A4 IVS10+12G>A is indicated as CYP3A4*1G. The clopidogrel active metabolite antagonizes the GI protein–coupled PY212 receptor resulting in irreversible blockade of ADP binding on platelets. See page 1895 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology , Angiolillo and colleagues report on the influence of CYP3A4 genotype on interpatient variability in clopidogrel responsiveness.4 The authors find that an intronic single nucleotide polymorphism (SNP) in the CYP3A4 gene, IVS10+12G>A (also called CYP3A4*1G), influences platelet reactivity …