DIAZEPAM METABOLISM IN NATIVE CHINESE POOR AND EXTENSIVE HYDROXYLATORS OF S-MEPHENYTOIN - INTERETHNIC DIFFERENCES IN COMPARISON WITH WHITE SUBJECTS

A single oral 5 mg dose of diazepam was given to 16 healthy native Chinese Han volunteers. Eight volunteers were extensive metabolizers of S-mephenytoin, and eight were poor metabolizers of S-mephenytoin. Plasma levels of diazepam and its demethyl metabolite were determined by HPLC in blood samples drawn during 4 weeks. There was no difference in diazepam disposition between the two phenotypes. However, the plasma half-life of demethyldiazepam was longer in poor metabolizers than in extensive metabolizers of mephenytoin (mean ± SD: 161 ± 37 and 116 ± 29 hours, respectively; p < 0.02). The plasma concentrations of demethyldiazepam at 7, 14, and 21 days after intake of diazepam were significantly higher in poor metabolizers than in extensive metabolizers. We compared the pharmacokinetic parameters of diazepam in Chinese subjects with our previously reported data from white subjects. The mean plasma half-life values of diazepam in Chinese extensive metabolizers (85.1 hours) and poor metabolizers (88.3 hours) were very similar to those in white subjects who were poor metabolizers (88.3 hours), and more than twice those in white subjects who were extensive metabolizers (40.8 hours). In parallel, the mean clearance of diazepam in Chinese subjects (independent of phenotype) was similar to that in white subjects who were poor metabolizers, but half that in white subjects who were extensive metabolizers. Chinese subjects had a slightly larger volume of distribution of diazepam than white subjects. This study showed that the metabolism of diazepam was slow in both extensive metabolizers and poor metabolizers of mephenytoin among Chinese subjects and similar to that in white subjects who were poor metabolizers. This indicates that there arc interethnic differences not only in the incidence of poor metabolizers of mephenytoin but also in the substrate specificity of the S-mephenytoin hydroxylase.