Pharmacokinetic and Pharmacodynamic Responses to Clopidogrel: Evidences and Perspectives

Abstract

Clopidogrel has significantly reduced the incidence of recurrent atherothrombotic events in patients with acute coronary syndrome (ACS) and in those undergoing percutaneous coronary intervention (PCI). However, recurrence events still remain, which may be partly due to inadequate platelet inhibition by standard clopidogrel therapy. Genetic polymorphisms involved in clopidogrel's absorption, metabolism, and the P2Y12 receptor may interfere with its antiplatelet activity. Recent evidence indicated that epigenetic modification may also affect clopidogrel response. In addition, non-genetic factors such as demographics, disease complications, and drug-drug interactions can impair the antiplatelet effect of clopidogrel. The identification of factors contributing to the variation in clopidogrel response is needed to improve platelet inhibition and to reduce risk for cardiovascular events. This review encompasses the most recent updates on factors influencing pharmacokinetic and pharmacodynamic responses to clopidogrel.

Keywords: clopidogrel; epigenetics; genetic polymorphisms; non-genetic factors; pharmacogenomics.

Figure 1

The metabolic pathway of clopidogrel and its targeted receptor. Intestinal absorption of the prodrug clopidogrel is limited by P-glycoprotein (P-gp). After absorption, the clopidogrel (inactive) is oxidized to 2-oxo clopidogrel (still inactive) by CYP450 enzymes. The 2-oxo clopidogrel is then transformed into active metabolites that will bind to P2Y12 receptor on platelet surfaces.