Key result
Proton pump inhibitors differentially inhibited the formation of active metabolites of clopidogrel (IC50 6-20 μm) and prasugrel (IC50 9-25 μm), decreasing their antiplatelet activities.
Why the study?
Do proton pump inhibitors differentially inhibit the metabolism and antiplatelet activities of clopidogrel and prasugrel in human liver microsomes?
Do proton pump inhibitors differentially inhibit the metabolism and antiplatelet activities of clopidogrel and prasugrel in human liver microsomes?
Proton pump inhibitors exhibit differential inhibitory effects on the metabolism and antiplatelet activities of clopidogrel and prasugrel in vitro, with omeprazole showing strong inhibition.
May inform mechanistic PPI-thienopyridine interactions; leaves open clinical relevance and differential effects on clopidogrel versus prasugrel.
The interaction between proton pump inhibitors (PPIs) and clopidogrel/prasugrel was investigated. The IC50 values of omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole on the metabolic ratios of 2-oxo-clopidogrel/clopidogrel, H4 (the active metabolite of clopidogrel)/2-oxo-clopidogrel and R-138727 (the active metabolite of prasugrel)/prasugrel thiolactone in human liver microsomes were determined. The antiplatelet activities of clopidogrel and prasugrel were measured with or without PPIs. As a result, most PPIs (except for pantoprazole) inhibited the formation of 2-oxo-clopidogrel with IC50 values of 20-32 μm and inhibited the formation of H4 with IC50 values of 6-20 μm. PPIs inhibited the formation of R-138727 with IC50 values of 9-25 μm. Among the tested PPIs, omeprazole exhibited the highest inhibitory potency on the formation of H4. Omeprazole, esomeprazole and rabeprazole exhibited the highest inhibitory potencies on the formation of R-138727. For platelet aggregation, omeprazole and lansoprazole show higher inhibitory effects on the antiplatelet activity of clopidogrel. On the other hand, omeprazole, esomeprazole and rabeprazole significantly decreased the antiplatelet activity of prasugrel thiolactone. These data indicate that PPIs differ in their effects of inhibiting the metabolism and antiplatelet activities of clopidogrel and prasugrel.
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Chen et al. (2012) studied this question. Proton pump inhibitors (PPIs) vs. Without PPIs was evaluated on Formation of active metabolites and antiplatelet activities. Proton pump inhibitors differentially inhibited the formation of active metabolites of clopidogrel (IC50 6-20 μm) and prasugrel (IC50 9-25 μm), decreasing their antiplatelet activities.
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