Reliability of the omeprazole hydroxylation index for CYP2C19 phenotyping:possible effect of age, liver disease and length of therapy

Aims To evaluate the reliability of the omeprazole hydroxylation index as a marker for polymorphic CYP2C19 activity in a Japanese population of health y young subjects (n = 78) and patients with peptic ulcer (n = 72). Methods Healthy subjects were administered a single dose oi omeprazole (20 mg), whereas patients received 20 mg daily for at least 1 week. The ratio o f the serum concentration of omeprazole to hydroxyomeprazole at 3 h postdos e was determined and used as a measure of CYP2C19 activity. The CYP2C19 wil d type (wt) gene and four mutant alleles associated with the poor metabolis er phenotype of (S)-mephenytoin, CYP2C19(star)2 in exon 5, CYP2C19(star)3 i n exon 4, CYP2C19m4 in exon 9, and CYP2C19m3 in the initial codon were anal ysed. Results In the healthy volunteer study there was complete concordance betwe en genotype and phenotype. However, eight of the patients who had the EM ge notype had a high value for their hydroxylation index, and were classified as phenotypic PMs. No CYP2C19m4 and CYP2C19m3 mutations were detected in th e eight mismatched patients. They were all genotypic heterozygous EMs, elde rly (greater than or equal to 65 years) and/or had hepatic disease. Therefo re, impaired CYP2C19 activity combined with partial saturation of omeprazol e 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 pr obe for polymorphic CYP2C19, it does not appear to be reliable enough for c linical application in Japanese patients.