Thienopyridine-Associated Drug-Drug Interactions: Pharmacologic Mechanisms and Clinical Relevance |
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Authors: | Jean-Sébastien Hulot Jean-Philippe Collet Gilles Montalescot |
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Institution: | Cardiovascular Research Center, Mount Sinai School of Medicine, New York, NY, USA. |
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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. |
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