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1. Xenobiotica. 2012 Feb 7. [Epub ahead of print]

Different effects of proton pump inhibitors and famotidine on the clopidogrel
metabolic activation by recombinant CYP2B6, CYP2C19 and CYP3A4.

Ohbuchi M, Noguchi K, Kawamura A, Usui T.

Drug Metabolism Research Laboratories, Drug Discovery Research, Astellas Pharma
Inc. , Osaka , Japan.

Inhibitory potential of proton pump inhibitors (PPIs) and famotidine, an H(2)
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 IC(50) of
12.8 μmol/L and more weakly inhibited that by CYP2B6 and CYP3A4. IC(50) 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 IC(50) 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.

PMID: 22313038 [PubMed - as supplied by publisher]