Metabolic disposition of pantoprazole, a proton pump inhibitor, in relation to S-mephenytoin 4′-hydroxylation phenotype and genotype

Objectives: To assess the possible relationship between the metabolic disposition of pantoprazole and genetically determined S-mephenytoin 4'-hydroxylation phenotype and genotype. Methods: The pharmacokinetic disposition of pantoprazole was investigated in 14 Japanese male volunteers (seven extensive and seven poor metabolizers of S-mephenytoin). All subjects received a single 40 mg oral dose of pantoprazole as the enteric-coated formulation. Results: An interphenotypic difference in the metabolic disposition of pantoprazole was observed: the mean values for area under the concentration-time curve (AUG), elimination half-life (t(1/2)), and apparent oral clearance were significantly (p < 0.01) greater, longer, and lower, respectively, in the poor metabolizers than in the extensive metabolizers. The mean AUC of pantoprazole sulfone was greater (P < 0.01) in the poor metabolizers than in the extensive metabolizers, whereas the mean AUC of the main demethylated metabolite (M2) was lower (p < 0.01) in the poor metabolizers than in the extensive metabolizers. A significant negative correlation was observed between the individual values for log(10)% urinary excretion of 4'-hydroxymephenytoin and AUC of pantoprazole (r(s) = -0.816; P < 0.005), The CYP2C19 genotyping test results were found to be in a complete accordance with the phenotypes. Conclusion: These data indicated that the metabolic disposition of pantoprazole is under the pharmacogenetic control of S-mephenytoin 4'-hydroxylase (CYP2C19).