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

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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