Genotypings of two mutations (*2 and *3) in CYP2C19 and the amino acid variants (Arg144/Cys, Tyr358/Cys, Ile359/Leu, and Gly417/Asp) in CYP2C9 were carried out in 140 unrelated Japanese subjects. Thirty-three subjects (23.6%) were genotypically identified as poor metabolizers of CYP2C19, and the allele frequencies of the CYP2C19*2 and CYP2C19*3 were 0.35 and 0.11, respectively. The authors' findings are in agreement with the 18% to 23% prevalence of poor metabolizers in the Japanese populations previously phenotyped. In CYP2C9, all subjects were homozygous (CYP2C9*1) for Arg144, Tyr358, Ile359, and Gly417, except for five subjects (3.6%) who were heterozygous for the Leu359 (CYP2C9*3). The frequencies of Arg144, Tyr358, Ile359, Leu359, and Gly417 variants were 1.0, 1.0, 0.982, 0.018, and 1.0, respectively. The low frequency of the Cys144 allele (CYP2C9*2) in the Japanese population is different from the frequency recently found in British subjects (allele frequency, 0.125 to 0.192). The results suggest that the known interindividual variations in the CYP2C9 sequence among Japanese subjects is small, and that Ile359/Leu is one possible site showing interracial polymorphism.

Summary:Purpose: The aim of this study was to clarify the effects of genetic polymorphisms of cytochrome P450 (CYP) 2C9 and 2C19 on the metabolism of phenytoin (PHT). In addition, a population pharmacokinetic analysis was performed.Methods: The genotype of CYP2C9 (Arg'44/Cys, Ile359/Leu) and CYP2C19 (*l, *2 or *3) in 134 Japanese adult patients with epilepsy treated with PHT were determined, and their serum concentrations of 5-(4-hydroxyphenyl)-5-phenylhydantoin @-HPPH) enantiomers, being major metabolites of PHT, were measured. A population pharmacokinetic analysis (NONMEM analysis) was performed to evaluate whether genetic polymorphism of CYP2C9/19 affects the clinical use of PHT by using the 336 dose-serum concentration data.Results: The mean maximal elimination rate (Vmax) was 42% lower in the heterozygote for Leu359 allele in CYP2C9, and the mean Michaelis-Menten constants (K,) in the heterozygous extensive metabolizers and the poor metabolizers of CYP2C19 were 22 and 54%, respectively, higher than those without the mutations in CYP2C9/19 genes. (R)-and (5')-p-HPPHPHT ratios were lower in patients with mutations in CYP2C9 or CYP2C19 gene than those in patients without rnutations.Conclusions: Although the hydroxylation capacity of PHT was impaired with mutations of CYP2C9/19, the impairment was greater for CYP2C9. In view of the clinical use of PHT, two important conclusions were derived from this population study. First, the serum PHT concentration in patients with the Leu359 allele in CYP2C9 would increase dramatically even at lower daily doses. Second, the patients with CYP2C19 mutations should be treated carefully at higher daily doses of PHT.Key Words: Phenytoin-CYP2C9-CYP2C19-Genetic polymorphism-NONMEM.Phenytoin (PHT), a widely prescribed anticonvulsant (AED), is a prochiral compound that is eliminated in humans almost entirely by cytochrome P450 (CYP)-mediated oxidation (1.2). Although the major advantage of its clinical use is that a relation between serum concentration and therapeutic effect has been established, it is sometimes difficult to adjust the dose of PHT to attain a therapeutic drug concentration because of the variability in its pharmacokinetic properties [e.g., capacity limited metabolism (3,4)]. The principal metabolic pathway is formation of 5-(4-hydroxyphenyl)-5-phenylhydantoin @-HPPH) that exists as (R)-and (S)-enantiomers and accounts for -90% of total urinary metabolites (5). The results bf recent human liver microsomal kinetic (2,6-8),

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The pharmacokinetic profile of omeprazole was examined in 27 healthy Japanese volunteers, and the results were analyzed in relation to genotype for the two mutations, CgammaP2C19m1 in exon 5 and CgammaP2C19m2 in exon 4, associated with the poor metabolizer phenotype. Of the 27 individuals analyzed, 10 were homozygous for the wild-type (wt) allele in both exon 5 and exon 4 (wt/wt; 37.0%, pattern GI), five were heterozygous for the CgammaP2C19m1 (wt/m1; 18.5%, G2), five were heterozygous for the CgammaP2C19m2 (wt/m2; 18.5%, G3), two were heterozygous for the two defects (m1/m2; 7.4%, G4), and five were homozygous for the CgammaP2C19m1 (m1/m1; 18.5%, G5). The allele frequencies of the m1 and m2 mutation were 0.31 and 0.13, respectively. A correlation between the rate of metabolism of omeprazole and genotype was observed. The mean clearance values of omeprazole in patterns G1, G2, G3, G4, and G5 were 1369.0, 332.7, 359.0, 70.8, and 89.5 ml/hr/kg, respectively. The relative area under the serum concentration-time curve (AUC) ratio of omeprazole to 5-hydroxyomeprazole in patterns G1, G2, G3, G4, and G5 was 1:2.8:3.4:16:17.2. A similar relation was observed in the omeprazole/5-hydroxyomeprazole serum concentration ratio, determined 3 hours after drug intake (1:3:4:18.8:20.3). There were significant (p < 0.05 to 0.01) differences in the disposition kinetics of omeprazole between the subjects with patterns G1, G2, and G3 and the subjects with patterns G4 and G5. The results indicate that the 5-hydroxylation pathway of omeprazole is clearly impaired in subjects with m1/m2 and m1/m1.