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

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Abstract
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 50 mg/kg for oral administration), rats (5, 10 and 20 mg/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) × maximum life‐span potential (MLP) (1 year/h) and log species body weight (W) (kg) (r=0.999; p=0.0015), log Cl (l/h) and log W (kg) (r=0.979; p=0.0209), and log apparent volume of distribution at steady state (Vss) (l) and log W (kg) (r=0.999; p=0.0009). The corresponding allometric equations were Cl×MLP=49.8 W0.861, Cl=5.20 W0.523 and Vss=4.46 W0.764. 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 © 2005 John Wiley & Sons, Ltd.