Impact of genetic and acquired alteration in cytochrome P450 system on pharmacologic and clinical response to clopidogrel.
Dual antiplatelet therapy with aspirin and clopidogrel has been shown to reduce subsequent cardiac events in patients with acute coronary syndrome or coronary artery stenting. Clopidogrel, a thienopyridine, is a prodrug that is transformed in vivo to an active metabolite by the cytochrome P450 (CYP) enzyme system. The genes encoding CYP enzymes are polymorphic. Recent data demonstrated patients carrying a genetic variant of CYP enzymes (e.g. CYP2C19) would have a higher rate of ischemic events than non-carriers due to an attenuation of the pharmacokinetic and pharmacodynamic responses to clopidogrel. Furthermore, concomitant gastrointestinal ulcer prophylaxis with a proton pump inhibitor (PPI) is commonly prescribed to patients because of the increased risk of bleeding with dual antiplatelet therapy. PPIs are extensively metabolized by the cytochrome P450 system and have been associated with decreased antiplatelet activity of clopidogrel. In this review, we will discuss the impact of CYP450 enzymes genetic variation and CYP450 pathway drug-drug interactions in pharmacological and clinical response to clopidogrel.
Ma
Terry K W
TK
Department of Medicine & Therapeutics, Chinese University of Hong Kong, Hong Kong.
Lam
Yat-Yin
YY
Tan
Victoria P
VP
Kiernan
Thomas J
TJ
Yan
Bryan P
BP
D001241:Aspirin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000077144:Clopidogrel; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D004347:Drug Interactions; D004351:Drug Resistance; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D019338:Polypharmacy; D054328:Proton Pump Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
D002121:Calcium Channel Blockers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010975:Platelet Aggregation Inhibitors; D054328:Proton Pump Inhibitors; D003577:Cytochrome P-450 Enzyme System; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin