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Use of omeprazole as a probe drug for CYP2C19 phenotype in Swedish Caucasians: comparison with S-mephenytoin hydroxylation phenotype and CYP2C19 genotype.
- Source :
-
Pharmacogenetics [Pharmacogenetics] 1995 Dec; Vol. 5 (6), pp. 358-63. - Publication Year :
- 1995
-
Abstract
- A single oral dose of omeprazole (20 mg) was given orally to 160 healthy Caucasian Swedish subjects and tested as a probe for CYP2C19. The study was nonrandomized and included seven subjects previously classified as poor metabolizers (PM) of S-mephenytoin. The ratio between the plasma concentrations of omeprazole and hydroxyomeprazole (metabolic ratio; 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 omeprazole on the two occasions were correlated (rs = 0.85; p < 0.0001). There was a significant correlation between the MR of omeprazole and the S/R mephenytoin ratio among 141 subjects, in whom both ratios were determined (rs = 0.63, p < 0.001). All seven PMs of S-mephenytoin had higher MRs of omeprazole (7.1-23.8) than extensive metabolizers (EM) (0.1-4.9). All 160 subjects and another 15 Caucasian Swedish PMs previously phenotyped with mephenytoin were analysed with respect to the presence of the CYP2C19m1 allele by PCR amplification of the intron 4/exon 5 junction followed by Sma I digestion. EMs heterozygous for the CYP2C19m1 gene had MRs of omeprazole and S/R ratios of mephenytoin that were higher than those of subjects who were homozygous for the wild-type allele (p = 0.0001). Nineteen of the 22 PMs were homozygous for the CYP2C19m1 gene. Three were heterozygous for this allele. Thus, 41 of the 44 alleles (93%) of PMs were defective CYP2C19m1. One of the remaining three PM alleles was subsequently found to contain the CYP2C19m2 mutation, which has earlier been shown to be associated with the PM phenotype in Oriental populations. In conclusion, the phenotype determined by omeprazole correlated with that of mephenytoin, and was in good agreement with the genotype.
- Subjects :
- 2-Pyridinylmethylsulfinylbenzimidazoles
Adult
Alleles
Cytochrome P-450 CYP2C19
Female
Genotype
Humans
Hydroxylation
Male
Middle Aged
Molecular Probes
Omeprazole administration & dosage
Omeprazole analogs & derivatives
Omeprazole pharmacokinetics
Pharmacogenetics
Phenotype
Sweden
White People genetics
Aryl Hydrocarbon Hydroxylases
Cytochrome P-450 Enzyme System genetics
Cytochrome P-450 Enzyme System metabolism
Mephenytoin metabolism
Mixed Function Oxygenases genetics
Mixed Function Oxygenases metabolism
Omeprazole metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0960-314X
- Volume :
- 5
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Pharmacogenetics
- Publication Type :
- Academic Journal
- Accession number :
- 8747407
- Full Text :
- https://doi.org/10.1097/00008571-199512000-00004