title: Thienopyridine-associated drug-drug interactions: pharmacologic mechanisms and clinical relevance.
abstract: The thienopyridines inhibit platelet activation and aggregation by directly inhibiting the platelet P2Y12 adenosine diphosphate receptor. The available thienopyridines are prodrugs and must be converted into active forms by the cytochrome P450 (CYP) enzyme system. An important portion of the variability in platelet response to clopidogrel is explained by the variability in plasma concentrations of the clopidogrel active metabolite. Several reports have thus progressively raised concerns about potential drug interactions as a result of inhibition or induction of CYP450 enzymes. Pharmacokinetics and pharmacodynamics studies have notably shown that concomitant use of clopidogrel and some proton pump inhibitors reduces the antiplatelet effect of clopidogrel. Several other drugs (metabolized through CYP3A4 such as statins or antifungals) similarly impact the pharmacologic response to clopidogrel. Conversely, agents that induce CYP activity increase clopidogrel responsiveness. However, the data supporting the clinical relevance of such pharmacological drug interactions have been controversial. This review will provide an overview of the mechanisms underlying thienopyridine-associated drug-drug interactions, and highlight the most recent developments in the field and propose guidance for the practitioner.
authors.affiliation: Cardiovascular Research Center, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Hulot
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Collet
authors.forename: Gilles
authors.initials: G
authors.lastname: Montalescot
mesh_terms: D000077144:Clopidogrel; D004347:Drug Interactions; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D054328:Proton Pump Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010975:Platelet Aggregation Inhibitors; D054328:Proton Pump Inhibitors; D011725:Pyridines; C446540:thienopyridine; D000077144:Clopidogrel; D013988:Ticlopidine