title: Differential inhibitory effects of proton pump inhibitors on the metabolism and antiplatelet activities of clopidogrel and prasugrel.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Hospital, School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan, 100.
authors.forename: Chia-Hao
authors.initials: CH
authors.lastname: Chen
authors.forename: Jyh-Chin
authors.initials: JC
authors.lastname: Yang
authors.forename: Yow-Shieng
authors.initials: YS
authors.lastname: Uang
authors.forename: Chun-Jung
authors.initials: CJ
authors.lastname: Lin
mesh_terms: D000077144:Clopidogrel; D004347:Drug Interactions; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D010976:Platelet Count; D000068799:Prasugrel Hydrochloride; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D013876:Thiophenes / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D054328:Proton Pump Inhibitors; D013876:Thiophenes; D000077144:Clopidogrel; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine