Genotyping of S-mephenytoin 4′-hydroxylation in an extended Japanese population*

Abstract

OBJECTIVE: To assess the genotype pattern of S-mephenytoin 4'-hydroxylation in an extended Japanese population. METHODS: One hundred eighty-six unrelated, healthy Japanese subjects were genotyped for S-mephenytoin 4'-hydroxylase (CYP2C19) according to a genotyping technique to identify the wild-type (wt) gene and two mutations, CYP2C19m1 in exon 5 and CYP2C19m2 in exon 4. Fourty-six of the 186 subjects genotyped were phenotyped with racemic mephenytoin using the conventional 8-hour urine analysis of 4'-hydroxymephenytoin. RESULTS: The frequency of poor metabolizers by the genotyping analysis was 18.8% (35 of the 186 subjects), consisting of 12 homozygous for CYP2C19m1 (m1/m1), three homozygous for CYP2C19m2 (m2/m2), and 20 heterozygous for the two defects (m1/m2). Thus the allele frequencies of CYP2C19m1 and CYP2C19m2 were calculated to be 0.29 and 0.13 (107 and 46 of the total of 372 alleles), respectively. Among the 46 subjects phenotyped, seven were identified as the poor metabolizers, with a log10 urinary excretion of 4'-hydroxymephenytoin of < 0.3% of the racemic dose. These seven subjects were genotyped as the individuals with the m1/m1 (two), m1/m2 (four) or m2/m2 (one) allele combination, indicating a complete concordance between the phenotyping and genotyping tests. CONCLUSION: The present genotyping test confirmed that the frequency of CYP2C19 mutant gene m1 is about 2.2 times greater than another mutant gene, m2, among Japanese poor metabolizers. The genotyping of CYP2C19 discriminates between the two S-mephenytoin 4'-hydroxylation phenotypes completely in the Japanese subjects.