Abstract
Inhibitory potential of proton pump inhibitors (PPIs) and famotidine, an H2 receptor antagonist, on the metabolic activation of clopidogrel was evaluated using recombinant CYP2B6, CYP2C19 and CYP3A4.
Formation of the active metabolite from an intermediate metabolite, 2-oxo-clopidogrel, was investigated by liquid chromatography–tandem mass spectrometry and three peaks corresponding to the pharmacologically active metabolite and its stereoisomers were detected.
Omeprazole potently inhibited clopidogrel activation by CYP2C19 with an IC50 of 12.8 μmol/L and more weakly inhibited that by CYP2B6 and CYP3A4. IC50 of omeprazole for CYP2C19 and CYP3A4 was decreased about two- and three-fold, respectively, by 30-min preincubation with NADPH.
Lansoprazole, esomeprazole, pantoprazole, rabeprazole and rabeprazole thioether, a major metabolite, also inhibited metabolic activation by CYP2C19, with an IC50 of 4.3, 8.9, 48.3, 36.2 and 30.5 μmol/L, respectively.
In contrast, famotidine showed no more than 20% inhibition of clopidogrel activation by CYP2B6, CYP2C19 and CYP3A4 at up to 100 μmol/L and had no time-dependent CYP2C19 and CYP3A4 inhibition.
These results provide direct evidence that PPIs inhibit clopidogrel metabolic activation and suggest that CYP2C19 inhibition is the main cause of drug–drug interaction between clopidogrel and omeprazole. Famotidine is considered as a safe anti-acid agent for patients taking clopidogrel.
Acknowledgements
The authors sincerely appreciate the advice and expertise of Kyoko Hyodo (Sales & Marketing Product Marketing, Astellas Pharma Inc.), Toshio Uemura (Pharmacology Research Labs, Drug Discovery Research, Astellas Pharma Inc.) and Dr. Takuya Hirata (Applied Pharmacology Research Labs, Drug Discovery Research, Astellas Pharma Inc.).
Declaration of interest
The authors are all employees of Astellas Pharma Inc., which is the manufacturer of famotidine.