Comparative pharmacokinetics of coumarin anticoagulants XLIV: Dose-dependent pharmacokinetics of warfarin in rats.

The purpose of this investigation was to determine the effect of dose on warfarin pharmacokinetics in rats. First, in a crossover experiment, rats received 14C-warfarin, 0.2 mg/kg iv, 12 hr after an injection of either nonradioactive warfarin (0.5 mg/kg) or saline solution. Warfarin concentrations in plasma declined triexponentially as a function of time. Pharmacokinetic analysis revealed that pretreatment with warfarin significantly decreased the apparent volume of distribution, total plasma clearance, and intrinsic plasma clearance of the drug. In the second part of the investigation, rats received single intravenous warfarin injections in the order of 0.1-1.0-0.1 or 1.0-0.1-1.0 mg/kg at 2-week intervals. The apparent volume of distribution, total plasma clearance, and intrinsic plasma clearance of the 1.0-mg/kg warfarin dose were appreciably lower than those of the 0.1-mg/kg dose. The decrease in the apparent volume of distribution of warfarin with increasing dose is consistent with the previously observed concentration dependence in hepatic uptake of the drug.