PHARMACOKINETICS OF OMEPRAZOLE (A SUBSTRATE OF CYP2C19) AND COMPARISON WITH 2 MUTANT ALLELES, C-UPSILON-P2C19(M1) IN EXON-5 AND C-UPSILON-P2C19(M2) IN EXON-4, IN JAPANESE SUBJECTS

The pharmacokinetic profile of omeprazole was examined in 27 healthy J apanese volunteers, and the results were analyzed in relation to genot ype for the two mutations, CYP2C19(ml) in exon 5 and CYP2C19(m2) in ex on 4, associated with the poor metabolizer phenotype. Of the 27 indivi duals analyzed, 10 were homozygous for the wild-type (wt) allele in bo th exon 5 and exon 4 (wt/wt; 37.0%, pattern G1), five were heterozygou s for the CYP2C19(ml) (wt/ml; 18.5%, G2), five were heterozygous for t he CYP2C19(m2) (wt/m2; 18.5%, G3), two were heterozygous for the two d efects (ml/m2; 7.4%, G4), and five were homozygous for the CYP2C19(ml) (ml/ml; 18.5%, G5). The allele frequencies of the mi and m2 mutation were 0.31 and 0.13, respectively. A correlation between the rate of me tabolism of omeprazole and genotype was observed. The mean clearance v alues of omeprazole in patterns G1, G2, G3, G4, and G5 were 1369.0, 33 2.7, 359.0, 70.8, and 89.5 ml/hr/kg, respectively. The relative area u nder the serum concentration-time curve (AUG) 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-hydroxyomepr azole 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) differenc es 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 cl early impaired in subjects with ml/m2 and ml/ml.