Comparison of the kinetic disposition and metabolism of E3810, a new proton pump inhibitor, and omeprazole in relation to S-mephenytoin 4'-hydroxylation status

Abstract

We studied the kinetic disposition and metabolism of E3810 [(+/-)-sodium 2-[[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl ]-1H- benzimidazole], a new proton pump inhibitor, and omeprazole in 15 Japanese male volunteers, six of whom were poor metabolizers and nine of whom were extensive metabolizers of S-mephenytoin. All received once-daily 20 mg doses of E3810 or omeprazole for 7 days in a randomized crossover manner, with a 3-week washout period between the two trial phases. The parent drugs and their principal metabolites in plasma and urine were measured on days 1 and 7 after drug administration. The mean values for area under the plasma concentration-time curve (AUC) of omeprazole were 6.3- and 4.4-fold greater, whereas those of E3810 were 1.8- and 1.9-fold greater in poor metabolizers than in extensive metabolizers after the first and final doses, respectively. Although the mean AUC values for both drugs were significantly (p < 0.01 or p < 0.05) greater in poor metabolizers than in extensive metabolizers, the difference in the AUC between the two groups was smaller after E3810 than after omeprazole administration. The AUC of omeprazole tended to increase with the repeated doses in extensive metabolizers, whereas no such change was observed for E3810. The urinary excretions of the principal metabolite(s) of two proton pump inhibitors also reflected the data derived from plasma samples in relation to S-mephenytoin 4'-hydroxylation status. We conclude that the metabolism of two proton pump inhibitors is under coregulatory control of S-mephenytoin 4'-hydroxylase (CYP2C19), but that the magnitude of CYP2C19-mediated metabolism appears to differ between the two drugs. In contrast to omeprazole, the metabolism of E3810 is less saturable in extensive metabolizers during the repetitive dosings.