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

Miyuki Kimura, Ichiro Ieiri, Yukiko Wada, Kohsuke Mamiya, Akinori Urae, Emiko Iimori, Terufumi Sakai, Kenji Otsubo, Shun Higuchi

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Abstract

Aims. To evaluate the reliability of the omeprazole hydroxylation index as a marker for polymorphic CYP2C19 activity in a Japanese population of healthy young subjects (n = 78) and patients with peptic ulcer (n = 72). Methods. Healthy subjects were administered a single dose of omeprazole (20 mg), whereas patients received 20 mg daily for at least 1 week. The ratio of the serum concentration of omeprazole to hydroxyomeprazole at 3 h postdose was determined and used as a measure of CYP2C19 activity. The CYP2C19 wild type (wt) gene and four mutant alleles associated with the poor metaboliser phenotype of (S)-mephenytoin, CYP2C19*2 in exon 5, CYP2C19*3 in exon 4, CYP2C19m4 in exon 9, and CYP2C19m3 in the initial codon were analysed. Results. In the healthy volunteer study there was complete concordance between genotype and phenotype. However, eight of the patients who had the EM genotype had a high value for their hydroxylation index, and were classified as phenotypic PMs. No CYP2C19m4 and CYP2C19m3 mutations were detected in the eight mismatched patients. They were all genotypic heterozygous EMs, elderly (≥ 65 years) and/or had hepatic disease. Therefore, impaired CYP2C19 activity combined with partial saturation of omeprazole 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 probe for polymorphic CYP2C19, it does not appear to be reliable enough for clinical application in Japanese patients.

Original languageEnglish
Pages (from-to)115-119
Number of pages5
JournalBritish journal of clinical pharmacology
Volume47
Issue number1
DOIs
Publication statusPublished - Jan 28 1999
Externally publishedYes

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Omeprazole
Hydroxylation
Liver Diseases
Mephenytoin
Exons
Healthy Volunteers
Therapeutics
Genotype
Phenotype
Cytochrome P-450 CYP2C19
Peptic Ulcer
Codon
Alleles
Mutation
Liver
Serum

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Reliability of the omeprazole hydroxylation index for CYP2C19 phenotyping : Possible effect of age, liver disease and length of therapy. / Kimura, Miyuki; Ieiri, Ichiro; Wada, Yukiko; Mamiya, Kohsuke; Urae, Akinori; Iimori, Emiko; Sakai, Terufumi; Otsubo, Kenji; Higuchi, Shun.

In: British journal of clinical pharmacology, Vol. 47, No. 1, 28.01.1999, p. 115-119.

Research output: Contribution to journalArticle

Kimura, Miyuki ; Ieiri, Ichiro ; Wada, Yukiko ; Mamiya, Kohsuke ; Urae, Akinori ; Iimori, Emiko ; Sakai, Terufumi ; Otsubo, Kenji ; Higuchi, Shun. / Reliability of the omeprazole hydroxylation index for CYP2C19 phenotyping : Possible effect of age, liver disease and length of therapy. In: British journal of clinical pharmacology. 1999 ; Vol. 47, No. 1. pp. 115-119.
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abstract = "Aims. To evaluate the reliability of the omeprazole hydroxylation index as a marker for polymorphic CYP2C19 activity in a Japanese population of healthy young subjects (n = 78) and patients with peptic ulcer (n = 72). Methods. Healthy subjects were administered a single dose of omeprazole (20 mg), whereas patients received 20 mg daily for at least 1 week. The ratio of the serum concentration of omeprazole to hydroxyomeprazole at 3 h postdose was determined and used as a measure of CYP2C19 activity. The CYP2C19 wild type (wt) gene and four mutant alleles associated with the poor metaboliser phenotype of (S)-mephenytoin, CYP2C19*2 in exon 5, CYP2C19*3 in exon 4, CYP2C19m4 in exon 9, and CYP2C19m3 in the initial codon were analysed. Results. In the healthy volunteer study there was complete concordance between genotype and phenotype. However, eight of the patients who had the EM genotype had a high value for their hydroxylation index, and were classified as phenotypic PMs. No CYP2C19m4 and CYP2C19m3 mutations were detected in the eight mismatched patients. They were all genotypic heterozygous EMs, elderly (≥ 65 years) and/or had hepatic disease. Therefore, impaired CYP2C19 activity combined with partial saturation of omeprazole 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 probe for polymorphic CYP2C19, it does not appear to be reliable enough for clinical application in Japanese patients.",
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T1 - Reliability of the omeprazole hydroxylation index for CYP2C19 phenotyping

T2 - Possible effect of age, liver disease and length of therapy

AU - Kimura, Miyuki

AU - Ieiri, Ichiro

AU - Wada, Yukiko

AU - Mamiya, Kohsuke

AU - Urae, Akinori

AU - Iimori, Emiko

AU - Sakai, Terufumi

AU - Otsubo, Kenji

AU - Higuchi, Shun

PY - 1999/1/28

Y1 - 1999/1/28

N2 - Aims. To evaluate the reliability of the omeprazole hydroxylation index as a marker for polymorphic CYP2C19 activity in a Japanese population of healthy young subjects (n = 78) and patients with peptic ulcer (n = 72). Methods. Healthy subjects were administered a single dose of omeprazole (20 mg), whereas patients received 20 mg daily for at least 1 week. The ratio of the serum concentration of omeprazole to hydroxyomeprazole at 3 h postdose was determined and used as a measure of CYP2C19 activity. The CYP2C19 wild type (wt) gene and four mutant alleles associated with the poor metaboliser phenotype of (S)-mephenytoin, CYP2C19*2 in exon 5, CYP2C19*3 in exon 4, CYP2C19m4 in exon 9, and CYP2C19m3 in the initial codon were analysed. Results. In the healthy volunteer study there was complete concordance between genotype and phenotype. However, eight of the patients who had the EM genotype had a high value for their hydroxylation index, and were classified as phenotypic PMs. No CYP2C19m4 and CYP2C19m3 mutations were detected in the eight mismatched patients. They were all genotypic heterozygous EMs, elderly (≥ 65 years) and/or had hepatic disease. Therefore, impaired CYP2C19 activity combined with partial saturation of omeprazole 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 probe for polymorphic CYP2C19, it does not appear to be reliable enough for clinical application in Japanese patients.

AB - Aims. To evaluate the reliability of the omeprazole hydroxylation index as a marker for polymorphic CYP2C19 activity in a Japanese population of healthy young subjects (n = 78) and patients with peptic ulcer (n = 72). Methods. Healthy subjects were administered a single dose of omeprazole (20 mg), whereas patients received 20 mg daily for at least 1 week. The ratio of the serum concentration of omeprazole to hydroxyomeprazole at 3 h postdose was determined and used as a measure of CYP2C19 activity. The CYP2C19 wild type (wt) gene and four mutant alleles associated with the poor metaboliser phenotype of (S)-mephenytoin, CYP2C19*2 in exon 5, CYP2C19*3 in exon 4, CYP2C19m4 in exon 9, and CYP2C19m3 in the initial codon were analysed. Results. In the healthy volunteer study there was complete concordance between genotype and phenotype. However, eight of the patients who had the EM genotype had a high value for their hydroxylation index, and were classified as phenotypic PMs. No CYP2C19m4 and CYP2C19m3 mutations were detected in the eight mismatched patients. They were all genotypic heterozygous EMs, elderly (≥ 65 years) and/or had hepatic disease. Therefore, impaired CYP2C19 activity combined with partial saturation of omeprazole 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 probe for polymorphic CYP2C19, it does not appear to be reliable enough for clinical application in Japanese patients.

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