COMPARISON OF THE KINETIC DISPOSITION AND METABOLISM OF E3810, A NEW PROTON PUMP INHIBITOR, AND OMEPRAZOLE IN RELATION TO S-MEPHENYTOIN 4'-HYDROXYLATION STATUS

We studied the kinetic disposition and metabolism of E3810 [(+/-)-sodi um hyipyridin-2-yl]methylsulfinyl]-1H-benzimidazole], a new proton pum p inhibitor, and omeprazole in 15 Japanese male volunteers, six of who m were poor metabolizers and nine of whom were extensive metabolizers of S-mephenytoin. All received once-daily 20 mg doses of E3810 or omep razole for 7 days in a randomized crossover manner, with a 3-week wash out period between the two trial phases. The parent drugs and their pr incipal metabolites in plasma and urine were measured on days 1 and 7 after drug administration. The mean values for area under the plasma c oncentration-time curve (AUG) of omeprazole were 6.3- and 4.4-fold gre ater, whereas those of E3810 were 1.8- and 1.9-fold greater in poor me tabolizers than in extensive metabolizers after the first and final do ses, respectively. Although the mean AUC values for both drugs were si gnificantly (p < 0.01 or p < 0.05) greater in poor metabolizers than i n extensive metabolizers, the difference in the AUC between the two gr oups was smaller after E3810 than after omeprazole administration. The AUC of omeprazole tended to increase with the repeated doses in exten sive metabolizers, whereas no such change was observed for E3810. The urinary excretions of the principal metabolite(s) of two proton pump i nhibitors also reflected the data derived from plasma samples in relat ion to S-mephenytoin 4'-hydroxylation status. We conclude that the met abolism of two proton pump inhibitors is under coregulatory control of S-mephenytoin 4'-hydroxylase (CYP2C19), but that the magnitude of CYP 2C19-mediated metabolism appears to differ between the two drugs. In c ontrast to omeprazole, the metabolism of E3810 is less saturable in ex tensive metabolizers during the repetitive dosings.