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 (AUC), elimination half‐life (t½), 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 log10% urinary excretion of 4′‐hydroxymephenytoin and AUC of pantoprazole (rS = −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). Clinical Pharmacology & Therapeutics (1997) 62, 619–628; doi: