Antiplatelet Drug Resistance and Drug-Drug Interactions: Role of Cytochrome P450 3A4

Abstract

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.

Methods for the quantitative evaluation and prediction of CYP enzyme induction using humanin vitrosystems

“…As for prodrugs, which require metabolic activation to exert their clinical effect, CYP enzyme induction may result in an enhanced clinical effect or toxicity. Enhanced anti-platelet activity of clopidogrel when co-administered with CYP3A4 inducers such as rifampicin and St. John's wort was reported [141].…”

Nuclear Receptors in Vascular Biology

“…oxysterols); all of which that have been implicated in atherosclerosis development [37,38]. In addition, PXR promotes the CYP3A4-dependent biotransformation of clopidogrel to its active metabolite, thus promoting its inhibitory action on platelet aggregation [39]. Through PXR activation vascular tissue was able to convert the inactive pro-drug clopidogrel to its active metabolite [5].…”

Clopidogrel: review of bioanalytical methods, pharmacokinetics/pharmacodynamics, and update on recent trends in drug–drug interaction studies

“…Several studies have been performed, many in the recent past, that examine the potential for interaction of clopidogrel from pharmacokinetic and/or pharmacodynamic perspective with other important agents (Caplain et al, 1999a;Peeters et al, 1999;Slugg et al, 2000;Mistsios et al, 2004;Ayalasomayajula et al, 2007;Brandt et al, 2007;Farid et al, 2007;Lau and Gurbel, 2006;Kim et al, 2008a,b;Small et al, 2008;Umemura et al, 2008).…”