Background and objectiveThe metabolic activity of cytochrome P450 (CYP) 2C19 is genetically determined, and the pharmacokinetics of omeprazole, a substrate for CYP2C19, are dependent on the CYP2C19 genotype. However, a discrepancy between the CYP2C19 genotype and omeprazole pharmacokinetics was reported in patients with liver disease or advanced cancer. The objective of the present study was to evaluate the effect of aging on the relationship between the CYP2C19 genotype and its phenotype.MethodsTwenty-eight elderly and 23 young Japanese volunteers were enrolled after being genotyped. Each subject received a single intravenous dose of omeprazole (10mg and 20mg for the elderly and the young groups, respectively) and blood samples were obtained up to 6 hours after dose administration to determine  the  plasma  concentrations  of  omeprazole  and  its  metabolites, 5-hydroxyomeprazole and omeprazole sulfone. Pharmacokinetic parameters were obtained by noncompartmental analysis. Linear regression models were used to examine the joint effects of covariates such as genotype, age, etc., on the pharmacokinetic parameters, and the pharmacokinetic parameters showing statistical significance were compared by ANOVA.ResultsThere were significant differences between genotypes in the area under the plasma concentration-time curve of the young group and the elderly group. The number of mutation alleles and age were significant covariates for systemic clearance (CL), but age was the only significant covariate for volume of distribution at steady state (Vss). There were significant age- and genotype-related differences  and  a  significant  age × genotype  interaction  in  CL  (20.6 ± 11.0/12.7 ± 4.0/3.2 ± 1.0 and 5.4 ± 4.0/3.7 ± 1.4/2.1 ± 0.7 L/h for homozygous extensive metabolisers [EMs]/heterozygous EMs/poor metabolisers [PMs] of the young and the elderly groups, respectively). In Vss, a significant difference was found  between  the  young  and  the  elderly  groups  (219 ± 115 and 107 ± 44.5 mL/kg, respectively), but not between three genotypes (178 ± 142, 173 ± 79 and 110 ± 51 mL/kg for homozygous EMs, heterozygous EMs and PMs, respectively).ConclusionThe elderly EMs showed wide variance in thein vivoCYP2C19 activity and were phenotypically closer to the elderly PMs than the young EMs were to the young PMs. Some of the elderly homozygous EMs, as well as heterozygous EMs, have a metabolic activity similar to PMs, and the CYP2C19 genotype may therefore not be as useful as phenotyping in the elderly.