caa a22 4500 475818113 CHVBK 20180406123814.0 cr unu---uuuuu 170329e20000301xx s 000 0 eng 10.1007/s002280050703 doi (NATIONALLICENCE)springer-10.1007/s002280050703 CYP2C19 polymorphism effect on phenobarbitone [Elektronische Daten] Pharmacokineties in Japanese patients with epilepsy: analysis by population pharmacokinetics [K. Mamiya, A. Hadama, E. Yukawa, I. Ieiri, K. Otsubo, H. Ninomiya, N. Tashiro, S. Higuchi] Objective: The aim of this study was to clarify the effect of genetic polymorphisms of CYP2C19 on the pharmacokinetics of phenobarbitone (PB) using a nonlinear mixed-effects model (NONMEM) analysis in Japanese adults with epilepsy. Methods: A total of 144 serum PB concentrations were obtained from 74 subjects treated with both PB and phenytoin but without valproic acid. All patients were classified into three groups by CYP2C19 genotyping: G1, G2 and G3 were homozygous for the wild type of CYP2C19 (*1/*1), heterozygous extensive metabolizers (EMs), (*1/*2 or *1/*3), and poor metabolizers (PMs), (*2/*2, *2/*3), respectively. All data were analyzed using NONMEM to estimate pharmacokinetic parameters of PB with respect to the CYP2C19 genotype. Results: Thirty-three patients belonged to G1 (44.6%), 35 to G2 (47.3%), and 6 to G3 (8.1%). The total clearance (CL) of PB significantly decreased by 18.8% in PMs (G3) relative to EMs (G1 and G2). The CL tended to be lower in G2 than in G1. Conclusion: In this study, we first demonstrated the effect of the CYP2C19 polymorphism on pharmacokinetics of PB by genotyping. The contribution of other metabolic enzymes in the metabolism of PB in humans remains to be elucidated; however, it appears that the disposition of PB is mediated in part by this enzyme. The estimated population clearance values in the three genotype groups can be used to predict the PB dose required to achieve an appropriate serum concentration in an individual patient. Springer-Verlag Berlin Heidelberg, 2000 Key words Phenobarbitone nationallicence CYP2C19 nationallicence Genetic polymorphism nationallicence Pharmacokinetics nationallicence NONMEM nationallicence Mamiya K. Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan e-mail: mamiya@shunsan.phar.kyushu-u.ac.jp Tel.: +81-92-6426659; Fax: +81-92-6426660, JP aut Hadama A. Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Fukuoka, 812-8582, Japan, JP aut Yukawa E. Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Fukuoka, 812-8582, Japan, JP aut Ieiri I. Department of Hospital Pharmacy, Faculty of Medicine, Tottori University, 36-1, Nishi-Machi, Yonago, 683-8349, Japan, JP aut Otsubo K. Department of Hospital Pharmacy, Faculty of Medicine, Tottori University, 36-1, Nishi-Machi, Yonago, 683-8349, Japan, JP aut Ninomiya H. Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan, JP aut Tashiro N. Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan, JP aut Higuchi S. Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Fukuoka, 812-8582, Japan, JP aut https://doi.org/10.1007/s002280050703 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s002280050703 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Mamiya K. Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan e-mail: mamiya@shunsan.phar.kyushu-u.ac.jp Tel.: +81-92-6426659; Fax: +81-92-6426660, JP aut NATIONALLICENCE 700 1- Hadama A. Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Fukuoka, 812-8582, Japan, JP aut NATIONALLICENCE 700 1- Yukawa E. Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Fukuoka, 812-8582, Japan, JP aut NATIONALLICENCE 700 1- Ieiri I. Department of Hospital Pharmacy, Faculty of Medicine, Tottori University, 36-1, Nishi-Machi, Yonago, 683-8349, Japan, JP aut NATIONALLICENCE 700 1- Otsubo K. Department of Hospital Pharmacy, Faculty of Medicine, Tottori University, 36-1, Nishi-Machi, Yonago, 683-8349, Japan, JP aut NATIONALLICENCE 700 1- Ninomiya H. Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan, JP aut NATIONALLICENCE 700 1- Tashiro N. Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan, JP aut NATIONALLICENCE 700 1- Higuchi S. Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Fukuoka, 812-8582, Japan, JP aut Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer