Comparative pharmacokinetics of coumarin anticoagulants. XLIX: Nonlinear tissue distribution of S-warfarin in rats.

The serum protein binding of the oral anticoagulant drug warfarin varies widely among rats and largely accounts for corresponding variations in the total serum clearance of the drug. The hepatic uptake of warfarin is concentration dependent despite the concentration independence of the free fraction of warfarin in serum over a wide concentration range. This investigation was designed to determine the distribution of the S enantiomer of warfarin in rats as a function of warfarin concentration, free fraction in serum, dose, and time. Two groups of rats, one with relatively low (0.0043) and the other with relatively high (0.0105) average serum free fraction values, were selected from a large number of adult male Sprague-Dawley rats. All animals received an iv injection of S-warfarin, either 0.25 or 1.0 mg/kg, and were sacrificed at intervals over a period of 10 d. Concentrations of S-warfarin in serum, liver, kidneys, muscle, and fat were determined by HPLC. The tissue:serum concentration ratio (T:S) of the drug was highly concentration dependent, but was independent of dose, time, and (except for fat) free fraction in serum. The T:S for fat was higher in animals with the larger serum free fraction values. The T:S of S-warfarin for the liver was greater than 10 at low concentrations and reached a limiting value of 0.25 at relatively high concentrations of the drug. In general, the T:S versus concentration profiles of S-warfarin are consistent with the presence of two classes of binding sites in the tissues, one with very high affinity and low capacity, the other with lower affinity and apparently unlimited capacity under the experimental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)