Uno Tsukasa, Shimizu Mikiko, Yasui-Furukori Norio, Sugawara Kazunobu, Tateishi Tomonori
Department of Clinical Pharmacology, Hirosaki University School of Medicine, Japan.
Br J Clin Pharmacol. 2006 Mar;61(3):309-14. doi: 10.1111/j.1365-2125.2005.02556.x.
Rabeprazole is known to be a substrate of CYP2C19. Our objective was to evaluate the possible effect of an inhibitor of CYP2C19, fluvoxamine, and compare the inhibitory effect of fluvoxamine on the metabolism of rabeprazole between CYP2C19 genotypes.
A two-way randomized double-blind, placebo-controlled crossover study was performed. Twenty-one volunteers, of whom seven were homozygous extensive metabolizers (EMs), eight were heterozygous EMs and six were poor metabolizers (PMs) for CYP2C19, received two 6-day courses of either fluvoxamine 50 mg or placebo daily in a randomized fashion with a single oral dose of rabeprazole 20 mg on day 6 in all cases. Plasma concentrations of rabeprazole and its metabolite rabeprazole thioether were monitored up to 24 h after dosing.
During placebo administration, the mean AUCs(0,infinity) of rabeprazole in homozygous EMs, heterozygous EMs and PMs were 882 (95% CI, 602, 1162) ng ml-1h , 1214 (975, 1453) ng ml-1 h and 2762 (2482, 3042) ng ml-1 h (P<0.001), respectively. Fluvoxamine treatment increased AUC(0,infinity) of rabeprazole and rabeprazole thioether by 2.8-fold (P<0.001) and 5.1-fold (P<0.01) in homozygous EMs, and by 1.7-fold (P<0.01) and 2.6-fold (P<0.01) in heterozygous EMs, and significantly prolonged the elimination half-life of rabeprazole and rabeprazole thioether in homozygous EMs and in heterozygous EMs, whereas no difference in any pharmacokinetic parameters was found in PMs. There was a significant difference in fluvoxamine-mediated percentage increase in AUC(0,infinity) of rabeprazole and rabeprazole thioether between CYP2C19 genotypes.
The present study indicates that there are significant drug interactions between rabeprazole and fluvoxamine in EMs of CYP2C19. It is predominantly involved in rabeprazole and rabeprazole thioether metabolism in EMs. Therefore, CYP2C19 is the key determinant of rabeprazole disposition in EMs.
雷贝拉唑是已知的CYP2C19底物。我们的目标是评估CYP2C19抑制剂氟伏沙明的可能作用，并比较氟伏沙明对不同CYP2C19基因型雷贝拉唑代谢的抑制作用。
进行了一项双因素随机双盲、安慰剂对照的交叉研究。21名志愿者，其中7名是CYP2C19的纯合子广泛代谢者（EMs），8名是杂合子EMs，6名是慢代谢者（PMs），以随机方式接受两个为期6天的疗程，每天服用50 mg氟伏沙明或安慰剂，所有病例在第6天单次口服20 mg雷贝拉唑。给药后长达24小时监测雷贝拉唑及其代谢产物雷贝拉唑硫醚的血浆浓度。
在服用安慰剂期间，雷贝拉唑在纯合子EMs、杂合子EMs和PMs中的平均AUC(0,∞)分别为882（95%CI，602,1162）ng ml-1h、1214（975,1453）ng ml-1 h和2762（2482,3042）ng ml-1 h（P<0.001）。氟伏沙明治疗使雷贝拉唑和雷贝拉唑硫醚的AUC(0,∞)在纯合子EMs中分别增加2.8倍（P<0.001）和5.1倍（P<0.01），在杂合子EMs中分别增加1.7倍（P<0.01）和2.6倍（P<0.01）,并显著延长了纯合子EMs和杂合子EMs中雷贝拉唑和雷贝拉唑硫醚的消除半衰期，而在PMs中未发现任何药代动力学参数有差异。CYP2C19基因型之间，氟伏沙明介导的雷贝拉唑和雷贝拉唑硫醚AUC(0,∞)增加百分比存在显著差异。
本研究表明在CYP2C19的EMs中雷贝拉唑与氟伏沙明之间存在显著的药物相互作用。它主要参与EMs中雷贝拉唑和雷贝拉唑硫醚的代谢。因此，CYP2C19是EMs中雷贝拉唑处置的关键决定因素。
