Polymorphic hydroxylation of S-mephenytoin and omeprazole metabolism in Caucasian and Chinese subjects

Abstract

Twelve Caucasian healthy men and women, of whom six were poor metabolizers (PMs) and six were extensive metabolizers (EMs) of S-mephenytoin, together with 13 Chinese healthy men and women (five PMs and eight EMs), received a single oral 20 mg dose of omeprazole. Plasma levels of omeprazole and its two main metabolites, omeprazole sulphone and hydroxyomeprazole, were determined by HPLC. The mean ( + SD) area under the plasma concentration-time curve (AUC) for omeprazole was 11.1 ±2.6 and 0.9 ± 0.4 μM h in the Caucasian PMs and EMs, respectively. Corresponding values for elimination half-life were 2.3 ± 0.4 and 0.7 ± 0.4 h. In the Chinese PMs and EMs the AUC of omeprazole as 13.3 + 5.6 and 2.6 ± 1.8 μM h. The AUCs of omeprazole were significantly higher in the Chinese EMs than in the Caucasian EMs possibly due to the higher proportion of heterozygotes in the former than in the latter group. The elimination half-life in the Chinese PMs and EMs was 2.4 ± 0.2 and 0.8 + 0.2 h -similar to the observations in the Caucasian subjects. The maximum plasma concentration of hydroxyomeprazole was five-fold and four-fold higher in EMs compared to PMs among Caucasians and Chinese, respectively. The elimination half-life of the hydroxy metabolite was also longer in PMs than in EMs in both populations. The ratio between AUC for omeprazole and AUC for hydroxyomeprazole was 11.9 ± 2.1 and 0.6 + 0.1 in Caucasian PMs and EMs, respectively. Corresponding values in the Chinese were 13.1 ±2.9 and 1.6 + 0.5. The AUCs of the sulphone metabolite were higher in PMs than in EMs among both Caucasians and Chinese. A longer half-life of the sulphone was also found in PMs compared to EMs. It is concluded that a major metabolic pathway of omeprazole, the formation of hydroxyomeprazole and at least partly also its elimination, cosegregates with the polymorphic metabolism of S-mephenytoin in both Caucasians and Chinese. The elimination, and perhaps part of the formation, of omeprazole sulphone also appears to be dependent on this polymorphic enzyme.