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

本文研究了氧氟沙星、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)对细胞色素P450(CYP)3A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，这些作用太弱，不能在临床状态下引发药物-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给药可显著降低茶碱的体内清除量，茶碱是一种通过抑制作用产生的CYP-1A底物。因此，具有抑制模式的FQS在临床状态下可能导致药物-药物相互作用。EM和CTD以竞争性方式抑制细胞色素P3A活性，但作用太弱，不能引起药物相互作用。然而，KCZ有效地抑制了细胞色素P3A…肝微粒体的活性增加。临床剂量的KCZ治疗明显降低了CYP底物的整体清除，包括咪达唑仑、硝苯地平和奎尼丁。该治疗将硝苯地平的口服生物利用度提高了约两倍。因此，提示在KCZ治疗过程中使用CyP3A底物可能会导致致命的毒性，如果底物的治疗范围相对较窄。利用体外实验的酶动力学参数来评估KCZ对静脉注射咪达唑仑的整体清除的影响，并与体内实验的结果进行比较。计算值与观测值非常接近。用酶动力学参数评价KCZ对硝苯地平的口服生物利用度和全身清除量的影响。药动学参数计算值与实测值吻合较好。因此，可以通过体外酶动力学参数来评价酶抑制剂对相应底物体内药代动力学的影响。较少

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