Abstract
Objectives: The relationship between the two CYP2C19 genotype mutations, CYP2C19m1 in exon 5 and CYP2C19m2 in exon 4, and omeprazole hydroxylation phenotype in healthy Japanese volunteers was studied. A simplified method for phenotyp-ing of CYP2C19 with omeprazole was also investigated.Methods: A total of 50 healthy Japanese volunteers were orally administered 20 mg omeprazole (OPZ) after overnight fasting. The area under the serum concentration-time curve (AUC) ratio of OPZ to 5-hydroxy OPZ (OPZ-OH) between 0 and 6 hr after dosing was calculated. After phenotyping, 28 subjects were analyzed for CYP2C19 genotype with the PCR-RFLP method.Results: The ratio of AUC (0-6hOPZ) to AUC (0-6hOPZ-OH) was significantly correlated with the OPZ/OPZ-OH serum concentration ratios, termed hydroxylation index (HI), at 2 and 3 hr after dosing. Twelve out of 50 subjects showed HI values of more than 6 at 3 hr after drug intake and were judged as poor metabolizers (PMs: 24%). Six out of 28 subjects were homozygous for the wild-type (wt/wt) allele in both exon 5 and exon 4 ; 11, heterozygous for the CYP2C19m1 (wt/m1); 5, heterozygous for the CYP2C19m2 (wt/m2); 5, homozygous for the CYP2C19m1 (m1/m1); 1, heterozygous for both defects (m1/m2). The homozygous genotype was compatible with the phenotype of the extensive metabolizer (EMs: wt/wt) and PMs (m1/m1). The heterozygous genotype, however, was not clearly compatible with the phenotype: one out of 11 with wt/m1 genotype was judged as PM. Five subjects with wt/m2 were EMs. The phenotype of one subject with m1/m2 could not be identified due to extremely low serum concentrations of OPZ and OPZ-OH.Discussion: From our findings, genotype and phenotype correlated well among the subjects. Further studies are needed to clarify the relationship between the CYP2C19 genotype and phenotype in subjects with a heterozygous genotype. Care should be taken in phenotyping CYP2C19 with OPZ using a few sampling points since gastric emptying time affects the systemic absorption of OPZ, and hence serum concentrations of the drug especially in the clinical situation are affected by co-administered medicines.
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Schedule a callMore From: Rinsho yakuri/Japanese Journal of Clinical Pharmacology and Therapeutics
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