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Possible pharmacokinetic drug-drug interaction by some drugs inhibiting cytochrome P450 activities in dogs

某些抑制狗细胞色素 P450 活性的药物可能存在药代动力学药物相互作用

基本信息

批准号：
14560262
负责人：
SHIMODA Minoru
金额：
$ 1.86万
依托单位：
National University Corporation Tokyo University of Agriculture and Technology
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

Possible inhibitory effects of several fluoroquinoloones(FQs), including ofloxacin, enrofloxacin, orbifloxacin, norfloxacin and ciprofloxacin on cytochrome P450(CYP) 1A and 3A activities, and of ketoconazole(KCZ), erythromycin(EM) and cimetidine(CTD) on CYP3A activities were examined in dogs. All of the FQs inhibited both CYP1A and 3A by a non-competitive manner in canine hepatic microsomes. However, the effects were too weak to elicit drug-drug interaction in clinical states. Of the FQs, ofloxacin, orbifloxacin and ciprofloxacin were mechanism inhibitors. The multiple treatment of ofloxacin at a clinical dose decreased significantly the total body clearance of theophylline, a CYP 1A substrate by mechanism passed inhibition. Therefore, FQs having the inhibitory mode might result in a drug-drug interaction in clinical states.EM and CTD inhibited CYP3A activities by a competitive manner, but the effects were too weak to elicit drug-drug interaction. However, KCZ potently inhibited CYP3A … More activities in hepatic microsomes. The treatment of KCZ at a clinical dose evidently decreased total body clearance of CYP substrates, including midazolam, nifedipin and quinidine. The treatment increased oral bioavailavility of nifedipin about twice. It is, therefore, suggested that the administration of CYP3A substrates during KCZ therapy may result in fatal toxicities, if the substrates have a relatively narrow therapeutic range.The effects of KCZ on total body clearance of intravenous midazolam were estimated using the enzyme kinetic parameters from in vitro experiments and compared with those from in vivo experiments. The calculated values were quite similar to the observed values. The effects of KCZ on oral bioavailability and total body clearance of nifedipine were also estimated using enzyme kinetic parameters. The calculated pharmacokinetic parameters were agreed well with observed values. It is, therefore, suggested that effects of enzyme inhibitors on in vivo pharmacokinetics of corresponding substrates can be estimated by in vitro enzyme kinetic parameters. Less

研究了氧氟沙星、恩诺沙星、奥比沙星、诺氟沙星和环丙沙星等氟喹诺酮类药物对犬细胞色素P450(CYP) 1A和3A活性的抑制作用，以及酮康唑（KCZ）、红霉素（EM）和西咪替丁（CTD）对CYP3A活性的抑制作用。所有FQs均以非竞争性方式抑制犬肝微粒体中的CYP1A和3A。然而，在临床状态下，效果太弱，不会引起药物相互作用。其中氧氟沙星、奥比沙星和环丙沙星为机制抑制剂。临床剂量的氧氟沙星多次治疗通过抑制机制显著降低了cyp1a底物茶碱的总清除率。因此，具有抑制模式的FQs可能导致临床状态下的药物相互作用。EM和CTD通过竞争方式抑制CYP3A活性，但作用太弱，无法引起药物-药物相互作用。而KCZ对CYP3A在肝微粒体中的活性有较强的抑制作用。临床剂量的KCZ治疗明显降低了机体对CYP底物的清除率，包括咪达唑仑、硝苯地平和奎尼丁。治疗后硝苯地平的口服生物利用度提高约2倍。因此，提示在KCZ治疗期间给予CYP3A底物，如果底物的治疗范围相对较窄，可能会导致致命的毒性。利用体外酶动力学参数估计KCZ对静脉注射咪达唑仑全身清除率的影响，并与体内酶动力学参数进行比较。计算值与观测值相当接近。利用酶动力学参数评价了KCZ对硝苯地平口服生物利用度和全身清除率的影响。计算的药代动力学参数与观测值吻合较好。因此，酶抑制剂对相应底物体内药代动力学的影响可以通过体外酶动力学参数来估计。少