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Publications (2)5.05 Total impact

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    ABSTRACT: The 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. Twenty-eight elderly and 23 young Japanese volunteers were enrolled after being genotyped. Each subject received a single intravenous dose of omeprazole (10 mg and 20 mg 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. There 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 x 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). The elderly EMs showed wide variance in the in vivo CYP2C19 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.
    No preview · Article · Feb 2005 · Clinical Pharmacokinetics
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    ABSTRACT: 内因性や外因性物質の酸化代謝を担うチトクロームP450(CYP)は複数の酵素からなる酵素群であり,その分子種である2C19(CYP2C19)はdiazepamやomeprazoleなど多くの薬物の代謝酵素として知られる.生体内CYP2C19活性には遺伝的多塑性があり,日本人の酵素活性欠損者はCYP2C19もしくは*3の変異遺伝子を有する.これまでの青森地域のABO式血液型の頻度分布や東北地方出身者におけるCYP2C19PMの頻度を検討した報告では青森県出身者と他地域出身者においてCYP2C19PMの頻度や変異遺伝子頻度が異なる可能性を示唆している.そこで今回下北半島の過疎地である川内町在住高齢者のCYP2C19変異遺伝子の頻度を検討し,これまでの日本人の報告と比較した.川内町出身の在住者108名を対象にCYP2C19変異遺伝子を検索した.今回得られた遺伝子型頻度はhomoEM:32.4%,hetEM:51.9%,PM:15.7%および変異遺伝子アリル頻度は*1:58.3%,*2:30.6%,*3:11.1%とこれまでの日本人の報告と有意の差を認めなかった.本研究の結果やこれまでの報告から,日本人においては出身地域によるCYP2C19変異遺伝子の頻度や遺伝子型頻度の差異は小さいと考えられた.
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