Antiplatelet drug resistance and drug-drug interactions: Role of cytochrome P450 3A4.
Antiplatelet therapy provided pivotal advances in the treatment of cardiovascular disease. Aspirin and thienopyridine, clopidogrel, is currently the treatment of choice in acute coronary syndromes and the prevention of thrombosis after coronary stent implantation. Despite the efficacy of this dual antiplatelet therapy in reduction of adverse coronary events in patients with acute coronary syndromes, complications persist in a subgroup of these patients. Emerging causes of aspirin and clopidogrel resistance may translate to increase risk for recurrent myocardial infarction, stroke, or cardiac related mortality. However, the mechanism of antiplatelet drug resistance remains incompletely characterized, and a sensitive and specific assay of aspirin and clopidogrel effect that reliably predicts treatment failure has not emerged. To date, evidence supporting antiplatelet drug resistance are pharmacokinetic response variability, drug-drug interaction through competitive inhibition a specific enzymatic pathway, genetic variability, and variability in the induction of enzymatic pathway in metabolic activation of prodrugs, like clopidogrel. Further investigation or guidelines are needed to optimize antiplatelet treatment strategies to identify and treat patients resistant to aspirin and/or clopidogrel.
Lau
Wei C
WC
Medical Director Cardiovascular Center Operating Rooms, Cardiovascular Anesthesiology, University of Michigan Health System, Ann Arbor, Michigan, USA. weiclau@umich.edu
Gurbel
Paul A
PA
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D001241:Aspirin / Q000378:metabolism / Q000494:pharmacology; D000077144:Clopidogrel; D004347:Drug Interactions; D004351:Drug Resistance; D006801:Humans; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology
D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C422408:CYP3A43 protein, human; D013988:Ticlopidine; D001241:Aspirin