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.

Aims The aim of this study was to clarify whether phenytoin (PHT) stereoselective hydroxylation cosegregates with (S)-mephenytoin phenotype. Methods A single dose of PHT (100 mg) was administered orally to six healthy Japanese subjects in whom the genotype and phenotype of CYP2C19 had been determined previously. The urinary excretion profiles of the metabolites of PHT, (R)-and (S)-p-HPPH [5-(4-hydroxyphenyl)-5-phenylhydantoin] up to 36 h postdose were compared between the two groups of poor metabolizers (PMs, n=3) and extensive metabolizers (EMs, n=3) with respect to CYP2C19. CYP2C9 genotype was also determined. Results All the alleles were found to be wild type (Arg 144 Tyr 358 Ile 359 Gly 417 ) in each subject. The mean value for cumulative urinary excretion of unchanged PHT was not significantly different between the PMs and the EMs. However, recovery of (R)-p-HPPH at 36 h was 3.5-fold lower and that of (S)-p-HPPH 1.3-fold lower in PMs than in EMs. Although the mean urinary excretion values for both metabolites were significantly lower in the PMs than in the EMs, the difference between the two groups was larger for (R)-p-HPPH. A significant negative correlation was observed between the hydroxylation index of omeprazole (the ratio between the serum concentrations of omeprazole and hydroxyomeprazole in blood samples drawn 3 h after drug intake) and the log 10 0-12 h urinary recovery of (R)-p-HPPH. Conclusions In humans, the 4∞-hydroxylation of PHT is highly stereoselective towards formation of the (S)-enantiomer. Thus, (S)-hydroxylation by CYP2C9 might be the major determinant of the disposition of PHT. However, these results support the hypothesis that the stereoselective hydroxylation pathway of PHT to form (R)-p-HPPH cosegregates with the CYP2C19 metabolic polymorphism.

Aims To evaluate the reliability of the omeprazole hydroxylation index as a marker for polymorphic CYP2C19 activity in a Japanese population of healthy young subjects (n=78) and patients with peptic ulcer (n=72). Methods Healthy subjects were administered a single dose of omeprazole (20 mg), whereas patients received 20 mg daily for at least 1 week. The ratio of the serum concentration of omeprazole to hydroxyomeprazole at 3 h postdose was determined and used as a measure of CYP2C19 activity. The CYP2C19 wild type (wt) gene and four mutant alleles associated with the poor metaboliser phenotype of (S)-mephenytoin, CYP2C19*2 in exon 5, CYP2C19*3 in exon 4, CYP2C19m4 in exon 9, and CYP2C19m3 in the initial codon were analysed. Results In the healthy volunteer study there was complete concordance between genotype and phenotype. However, eight of the patients who had the EM genotype had a high value for their hydroxylation index, and were classified as phenotypic PMs. No CYP2C19m4 and CYP2C19m3 mutations were detected in the eight mismatched patients. They were all genotypic heterozygous EMs, elderly (≥65 years) and/or had hepatic disease. Therefore, impaired CYP2C19 activity combined with partial saturation of omeprazole metabolism during multiple dosing may have contributed to the discrepancy between CYP2C19 genotyping and phenotyping. Conclusion Although omeprazole has been used instead of mephenytoin as a probe for polymorphic CYP2C19, it does not appear to be reliable enough for clinical application in Japanese patients.Keywords: CYP2C19, omeprazole hydroxylation index, genotype, phenotype, clinical applicability been demonstrated, its clinical application has not been Introduction investigated. In the present study, we compared CYP2C19 phenotype using the omeprazole hydroxylOmeprazole, a proton pump inhibitor, is metabolised by the liver to two major plasma metabolites, hydroxyomepation index to genotype in populations of healthy volunteers and patients with peptic ulcer. razole and omeprazole sulphone [1]. In vivo and in vitro studies have indicated that the formation of hydroxyomeprazole is mediated by CYP2C19, with a minor contriMethods bution from CYP3A4 [1][2][3][4]. Because the mephenytoin Subjects and study protocol S/R enantiomeric ratio is significantly correlated with Seventy eight unrelated healthy Japanese subjects particithe omeprazole hydroxylation index (the ratio of omeprapated in the first study. The subjects ranged in age from zole to hydroxyomeprazole in serum 3 h post-dose) [5], 20 to 47 years (median with 25% and 75% quartiles 23.0, omeprazole is used by some to assess CYP2C19 phenotype 21.0 and 30.0), and 58 of them were male. Each subject [6][7][8]. Although the reliability of the omeprazole hydroxhad no antecedent history of significant illness or ylation index for phenotyping healthy volunteers has medication, or hypersensitivity to any drugs. A physical examination, blood chemistry screening, a complete blood