Clopidogrel resistance: pharmacokinetic or pharmacogenetic?

Clopidogrel is important for the management of acute coronary syndromes and, along with aspirin, is recommended in the American College of Cardiology/American Heart Association guideline. It is also used along with aspirin, during the placement of coronary artery stents. Clopidogrel resistance was recognized in such procedures, as several patients did not have the anticipated platelet aggregation response to an ex vivo adenosine diphosphate challenge. From the EXCELSIOR study, which investigated the phenomenon, it was appreciated that it was present prior to treatment with clopidogrel and was therefore an intrinsic property of the patient's platelets. From other studies, it was appreciated that the patients who had clopidogrel resistance had a defective allele *2/ in the CYP2C19 gene. Furthermore, there was a dose response evident in that the homozygotes CYP2C19*2/*2 had platelets that responded even less well to clopidogrel than the heterozygotes CYP2C19*2 that responded less well than the wild-type homozygote. The involvement of the phenomenon with CYP2C19 led some to believe that it was a pharmacokinetic issue. However, the major oxidative metabolic pathway for clopidogrel by which the reactive intermediate is formed is CYP3A4. It is suggested that there is a linkage between a polymorphism of the platelet receptor P2Y12 and the polymorphism of CYP2C19.