抄録
Interethnic differences for the frequencies of poor metabolizers (PMs) of sparteine/metoprolol and mephenytoin type of oxidation were studied in the Japanese, Korean, Indonesian and Chinese populations. The frequencies of PMs for the α-hydroxylation of metoprolol in Japanese, Korean, Indonesian and Chinese populations (0-0.7%) were ten-times less than that of Caucasians (7%). On the other hand, the frequencies of PMs for the 4'-hydroxylation of mephenytoin were much higher in Japanese (20%), Korean (13%), Indonesian (15%) and Chinese (18%) populations when compared with the Caucasian populations (3%). These differences of the incidence of PMs of metoprolol and mephenytoin oxidation polymorphism between Oriental and Caucasian populations suggest that drugs which are established for their safety in European or North American countries cannot always be introduced safely to Oriental countries and vice versa. Since mephenytoin type of drug oxidation is particularly important for assessing drug safety in Japanese population, we developed a simple assay of S-mephenytoin 4'-hydroxylation activities in human liver microsomes. Using this assay method, we found that 5-hydroxylation of omeprazole is mainly catalyzed by CYP2C19. We confirmed the finding obtained from the in vitro study using human liver microsomes, by in vivo panel study, which showed that mean AUC of omeprazole is significantly higher in PMs than extensive metabolizers of mphenytoin. The findings suggest that in vitro method using human liver microsomes is useful to assess an involvement of CYP2C19, an isoform of cytochrome P450 showing marked genetic polymorphism in Japanese population, in the metabolism of drugs under development.
