Pharmacokinetics of omeprazole (a substrate of CYP2C19) and comparison with two mutant alleles, CYP2C19m1 in exon 5 and CYP2C19m2 in exon 4, in Japanese subjects*
| Autor: | Koichi Nakamura, Ichiro Ieiri, Shin Irie, Yukiko Wada, Akinori Urae, Takahiro Kubota, Miyuki Kimura, Shin’ichi Yoshioka, Kosuke Mamiya, Shigeyuki Nakano, Shun Higuchi, Toshiaki Amamoto |
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| Rok vydání: | 1996 |
| Předmět: |
Adult
Male medicine.medical_specialty Genotype CYP2C19 Pharmacology Biology 2-Pyridinylmethylsulfinylbenzimidazoles Mixed Function Oxygenases Exon Asian People Cytochrome P-450 Enzyme System Japan Pharmacokinetics Internal medicine medicine Humans Pharmacology (medical) Enzyme Inhibitors Allele Allele frequency Alleles Omeprazole Exons Middle Aged Phenotype Cytochrome P-450 CYP2C19 Endocrinology Mutation Female Aryl Hydrocarbon Hydroxylases Half-Life medicine.drug |
| Zdroj: | Clinical Pharmacology & Therapeutics. 59:647-653 |
| ISSN: | 1532-6535 0009-9236 |
| DOI: | 10.1016/s0009-9236(96)90004-1 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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