USE OF OMEPRAZOLE AS A PROBE DRUG FOR CYP2C19 PHENOTYPE IN SWEDISH CAUCASIANS - COMPARISON WITH S-MEPHENYTOIN HYDROXYLATION PHENOTYPE AND CYP2C19 GENOTYPE

A single oral dose of omeprazole (20 mg) was given orally to 160 healt hy Caucasian Swedish subjects and tested as a probe for CYP2C19. The s tudy was nonrandomized and included seven subjects previously classifi ed as poor metabolizers (PM) of S-mephenytoin. The ratio between the p lasma concentrations of omeprazole and hydroxyomeprazole (metabolic ra tio; MR) was determined by HPLC in a blood sample drawn 3 h after drug intake. In 17 subjects the test was repeated and the MRs of omeprazol e on the two occasions were correlated (r(s) = 0.85; p < 0.0001). Ther e was a significant correlation between the MR of omeprazole and the S IR mephenytoin ratio among 141 subjects, in whom both ratios were dete rmined (r(s) = 0.63, p < 0.001), All seven PMs of S-mephenytoin had hi gher MRs of omeprazole (7.1-23.8) than extensive metabolizers (EM) (0. 1-4.9), All 160 subjects and another 15 Caucasian Swedish PMs previous ly phenotyped with mephenytoin were analysed with respect to the prese nce of the CYP2C19m(1) allele by PCR amplification of the intron 4/exo n 5 junction followed by Smn I digestion, EMs heterozygous for the CYP 2C19m(1) gene had MRs of omeprazole and SIR ratios of mephenytoin that were higher than those of subjects who were homozygous for the wild-t ype allele (p = 0.0001), Nineteen of the 22 PMs were homozygous for th e CYP2C19m(1) gene, Three were heterozygous for this allele, Thus, 41 of the 44 alleles (93%) of PMs were defective CYP2C19m(1), One of the remaining three PM alleles was subsequently found to contain the CYP2C 19m(1) mutation, which has earlier been shown to be associated with th e PM phenotype in Oriental populations, In conclusion, the phenotype d etermined by omeprazole correlated with that of mephenytoin, and was i n good agreement with the genotype.