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