The anticoagulant warfarin exemplifies a type of drug that exhibits high affinity to pharmacologic target sites of limited capacity, resulting in unusual concentration-dependent distribution and elimination properties. The time course of warfarin concentrations in the serum, liver, kidneys, muscle, and abdominal fat of male Sprague-Dawley rats was determined by high-performance liquid chromatography after IV injection of a 0.25 or 1.0 mg/kg dose. The rats were preclassified on the basis of their serum free fraction of warfarin; animals with free fraction values of approximately 0.004 and 0.01 and corresponding differences in elimination half-life were selected for study, yielding four experimental groups. Several rats of each group were sacrificed periodically over approximately 80-240 h for determination of drug concentrations. S-warfarin concentrations in serum declined apparently exponentially over at least one order of magnitude. During this time, concentrations in all other assayed tissues declined much more slowly. In another experiment, S-warfarin concentrations in serum and liver were followed for approximately 50 days after IV injection of a 1 mg/kg dose. This revealed a terminal, very slow elimination phase in serum nearly parallel to the decline in liver drug concentrations. Simultaneous physiologic modeling of all data (30 equations) using ADAPT II (Biomedical Simulations Resource, Los Angeles, CA), with intrinsic clearance, the dissociation constant of the warfarin-high affinity binding site complex, and two binding parameters for the (unassayed) remainder tissue compartment as parameters of unknown value, yielded very good fittings and parameter estimates with relatively small standard deviations. The unusual dose-dependent accumulation characteristics of this type of drug during continuous infusion are demonstrated by computer simulation of published results of warfarin infusions in rats. Utilization of a model premised on similar target-mediated drug disposition also allowed characterization of data from the literature for racemic warfarin pharmacokinetics in man. Copyright 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92:985-994, 2003