Pharmacokinetics of omeprazole (a substrate of CYP2C19) and comparison with two mutant alleles, CYP2C19(m1) in exon 5 and CYP2C19(m2) in exon 4, in Japanese subjects

Ichiro Ieiri, Takahiro Kubota, Akinori Urae, Miyuki Kimura, Yukiko Wada, Kosuke Mamiya, Shinichi Yoshioka, Shin Irie, Toshiaki Amamoto, Koichi Nakamura, Shigeyuki Nakano, Shun Higuchi

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Abstract

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, CYP2C19(m1) in exon 5 and CYP2C19(m2) 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 G1), five were heterozygous for the CYP2C19(m1) (wt/ml; 18.5%, G2), five were heterozygous for the CYP2C19(m2) (wt/m2; 18.5%, G3), two were heterozygous for the two defects (m1/m2; 7.4%, G4), and five were homozygous for the CYP2C19(m1) (ml/ml; 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.

Original languageEnglish
Pages (from-to)647-653
Number of pages7
JournalClinical Pharmacology and Therapeutics
Volume59
Issue number6
DOIs
Publication statusPublished - Jun 1 1996

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Omeprazole
Exons
Pharmacokinetics
Alleles
Genotype
Mutation
Hydroxylation
Cytochrome P-450 CYP2C19
Serum
Gene Frequency
Area Under Curve
Healthy Volunteers
Phenotype
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

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Pharmacokinetics of omeprazole (a substrate of CYP2C19) and comparison with two mutant alleles, CYP2C19(m1) in exon 5 and CYP2C19(m2) in exon 4, in Japanese subjects. / Ieiri, Ichiro; Kubota, Takahiro; Urae, Akinori; Kimura, Miyuki; Wada, Yukiko; Mamiya, Kosuke; Yoshioka, Shinichi; Irie, Shin; Amamoto, Toshiaki; Nakamura, Koichi; Nakano, Shigeyuki; Higuchi, Shun.

In: Clinical Pharmacology and Therapeutics, Vol. 59, No. 6, 01.06.1996, p. 647-653.

Research output: Contribution to journalArticle

Ieiri, Ichiro ; Kubota, Takahiro ; Urae, Akinori ; Kimura, Miyuki ; Wada, Yukiko ; Mamiya, Kosuke ; Yoshioka, Shinichi ; Irie, Shin ; Amamoto, Toshiaki ; Nakamura, Koichi ; Nakano, Shigeyuki ; Higuchi, Shun. / Pharmacokinetics of omeprazole (a substrate of CYP2C19) and comparison with two mutant alleles, CYP2C19(m1) in exon 5 and CYP2C19(m2) in exon 4, in Japanese subjects. In: Clinical Pharmacology and Therapeutics. 1996 ; Vol. 59, No. 6. pp. 647-653.
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abstract = "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, CYP2C19(m1) in exon 5 and CYP2C19(m2) 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 G1), five were heterozygous for the CYP2C19(m1) (wt/ml; 18.5{\%}, G2), five were heterozygous for the CYP2C19(m2) (wt/m2; 18.5{\%}, G3), two were heterozygous for the two defects (m1/m2; 7.4{\%}, G4), and five were homozygous for the CYP2C19(m1) (ml/ml; 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.",
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T1 - Pharmacokinetics of omeprazole (a substrate of CYP2C19) and comparison with two mutant alleles, CYP2C19(m1) in exon 5 and CYP2C19(m2) in exon 4, in Japanese subjects

AU - Ieiri, Ichiro

AU - Kubota, Takahiro

AU - Urae, Akinori

AU - Kimura, Miyuki

AU - Wada, Yukiko

AU - Mamiya, Kosuke

AU - Yoshioka, Shinichi

AU - Irie, Shin

AU - Amamoto, Toshiaki

AU - Nakamura, Koichi

AU - Nakano, Shigeyuki

AU - Higuchi, Shun

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N2 - 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, CYP2C19(m1) in exon 5 and CYP2C19(m2) 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 G1), five were heterozygous for the CYP2C19(m1) (wt/ml; 18.5%, G2), five were heterozygous for the CYP2C19(m2) (wt/m2; 18.5%, G3), two were heterozygous for the two defects (m1/m2; 7.4%, G4), and five were homozygous for the CYP2C19(m1) (ml/ml; 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.

AB - 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, CYP2C19(m1) in exon 5 and CYP2C19(m2) 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 G1), five were heterozygous for the CYP2C19(m1) (wt/ml; 18.5%, G2), five were heterozygous for the CYP2C19(m2) (wt/m2; 18.5%, G3), two were heterozygous for the two defects (m1/m2; 7.4%, G4), and five were homozygous for the CYP2C19(m1) (ml/ml; 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.

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