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Inhibition of CYP2C19 and CYP3A4 by Omeprazole Metabolites and their Contribution to Drug-Drug Interactions.


Drug Metab Dispos. 2013 Apr 25;


Authors: Shirasaka Y, Sager JE, Lutz JD, Davis C, Isoherranen N


Abstract

The aim of this study was to evaluate the contribution of metabolites to drug-drug interactions (DDI) using the inhibition of CYP2C19 and CYP3A4 by omeprazole and its metabolites as a model. Of the metabolites identified in vivo, 5-hydroxyomeprazole, 5'-O-desmethylomeprazole, omeprazole sulfone and carboxyomeprazole had an AUCm/AUCp ≥ 0.25 when either total or unbound concentrations were measured following a single 20 mg dose of omeprazole in a cocktail. All of the metabolites inhibited CYP2C19 and CYP3A4 reversibly. In addition omeprazole, omeprazole sulfone and 5'-O-desmethylomeprazole were mechanism-based inhibitors (MBI) of CYP2C19 while omeprazole and 5'-O-desmethylomeprazole were found to be MBIs of CYP3A4. Reversible [I]/Ki ratios and irreversible λ/kdeg ratios were used to evaluate whether characterization of the metabolites affected DDI risk assessment. Identifying omeprazole as an MBI of both CYP2C19 and CYP3A4 was the most important factor in DDI risk assessment. Consideration of reversible inhibition by omeprazole and its metabolites would not identify DDI risk with CYP3A4, and with CYP2C19 reversible inhibition values would only identify DDI risk if the metabolites are included in the assessment. Based on inactivation data, CYP2C19 and CYP3A4 inactivation by omeprazole would be sufficient to identify risk, but metabolites were predicted to contribute 30-63% to the in vivo hepatic interactions. Hence, consideration of metabolites may be important in quantitative predictions of in vivo DDIs. The results of this study show that while metabolites contribute to in vivo DDIs their relative abundance in circulation or logP values do not predict their contribution to in vivo DDI risk.

PMID: 23620487 [PubMed - as supplied by publisher]