An in vitro investigation into the mechanism of the clinically relevant drug-drug interaction between omeprazole or esomeprazole and clopidogrel
Abstract
Clopidogrel is a thienopyridine antiplatelet prodrug that was approved by the US FDA in 1997 and quickly supplanted ticlopidine as the primary drug therapy for reducing atherothrombotic events. It is converted to its pharmacologically active metabolite H4, which irreversibly inactivates the P2Y12 receptor on platelets, through two sequential reactions that are catalyzed mainly by CYP2C19. Common clinical practice involved the coadministration of a proton pump inhibitor (PPI, including omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole) with clopidogrel to decrease the risk of upper gastrointestinal bleeding. This practice was formalized for high risk patients by the American Heart Association (and others) in 2008. By 2009, numerous publications described an unexpected decrease in clopidogrel efficacy when coadministered with PPIs, prompting both the US Food & Drug Administration (FDA) and European Medicines Agency (EMA) to issue recommendations discouraging the concomitant use of PPIs and clopidogrel. Proton pump inhibitors are also metabolized by CYP2C19. It seemed reasonable to conclude that, despite their relatively short plasma half-lives, PPIs might competitively inhibit CYP2C19, thereby reducing the efficacy of clopidogrel. In 2010, as numerous publications emerged, both regulatory agencies restricted subsequent warnings to only omeprazole and esomeprazole. The interaction between clopidogrel and PPIs, and the potential mechanisms responsible for it,…
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