Interspecies pharmacokinetic scaling of oltipraz in mice, rats, rabbits and dogs, and prediction of human pharmacokinetics

Dose-independent pharmacokinetics of oltipraz after intravenous and/or oral administration at various doses to mice, rats, rabbits and dogs were evaluated. After both intravenous and/or oral administration of oltipraz to mice (5, 10 and 20 mg/kg for intravenous and 15, 30 and 50mg/kg for oral administration), rats (5, 10 and 20mg/kg for intravenous and 25, 50 and 100 mg/kg for oral administration), rabbits (5, 10 and 30 mg/kg for intravenous administration) and dogs (5 and 10 mg/kg for intravenous and 50 and 100 mg/kg for oral administration), the total area under the plasma concentration-time curve from time zero to time infinity (AUC) values of oltipraz were dose-proportional in all animals studied. Animal scale-up of some pharmacokinetics parameters of oltipraz was also performed based on the parameters after intravenous administration at a dose of 10 mg/kg to mice, rats, rabbits and dogs. Linear relationships were obtained between log time-averaged total body clearance (Cl) x maximum life-span potential (MLP) (1 year/h) and log species body weight (W) (kg) (r = 0.999; p = 0.0015), log Cl (1/h) and log W (kg) (r = 0.979; p = 0.0209), and log apparent volume of distribution at steady state (V-ss) (1) and log W (kg) (r = 0.999; p = 0.0009). The corresponding allometric equations were Cl x MLP = 49.8 W-0.861. 861, Cl = 5.20 W-0.523 and V-ss = 4.46 W-0.764. Interspecies scale-up of plasma concentration-time data for the four species using pharmacokinetic time of dienetichron resulted in similar profiles. In addition, concentrations of oltipraz in a plasma concentration-time profile for humans predicted using the four animal data fitted to the dienetichron time transformation of animal data. Copyright (c) 2005 John Wiley & Sons, Ltd.