EVIDENCE THAT POOR METABOLIZERS OF (S)-MEPHENYTOIN COULD BE IDENTIFIED BY HAPLOTYPES OF CYP2C19 IN JAPANESE

(S)-Mephenytoin is metabolized by CYP2C19. The purpose of this study w as to examine availability of phenotyping of poor metabolizers (PMs) o f (S)-mephenytoin by polymerase chain reaction(PCR)/restriction enzyme genotyping of CYP2C19 in a Japanese population. We genotyped 217 unre lated healthy Japanese for functionally defective alleles, CYP2C19m1 a nd CYP2C19m2. The frequencies of the wild type (W-m1) and CYP2C19m1 we re 0.726 and 0.274, and the wild type(W-m2) and CYP2C19m2 were 0.892 a nd 0.108 respectively, Although the observed numbers of three genotype s were very similar to those estimated according to the Hardy-Weinberg equilibrium for each defect, CYP2C19m2 was not detected in m2 homozyg otes, and CYP2C19m1 was not detected in m2 homozygotes. Two defects we re inherited separately in four families indicating CYP2C19m1 and m2 s egregate independently at the same gene locus, Based on these data, we calculated the haplotype frequencies of W-m1-W-m2, CYP2C19m1-W-m2 and W-m1-CYP2C19m2 to be 0.618, 0.274 and 0.108 respectively, frequencies of homozygotes for CYP2C19m1 and CYP2C19m2 and compound heterozygotes associated with the PM phenotype, were calculated to be 7.5, 1.2 and 5.9% respectively, In total, 14.6% of Japanese are estimated to be PMs , No significant difference was observed between the frequencies of PM s calculated from our results and that identified by urinary S/R ratio (18%) (p>0.05, chi 2=0.545, f(d)=1). Our data indicate that Japanese PMs of (S)-mephenytoin could be identified by PCR-based genotyping of CYP2C19.