Comparative Pharmacokinetics of Coumarin Anticoagulants XIV: Relationship between Protein Binding, Distribution, and Elimination Kinetics of Warfarin in Rats

The relationships between the protein binding, distribution in the body, and kinetics of elimination of warfarin were studied. Individual rats eliminated warfarin by apparent firstorder kinetics, with a biological half-life of 5.9–41hr and a total plasma clearance of 2.4–22ml kg−1hr−1. There is a strong positive correlation between the apparent volume of distribution (Vd) and the elimination rate constant (kel). There was no apparent concentration dependence of warfarin binding to serum proteins over a wide concentration range, but there were pronounced intersubject variations in protein binding, with the free fraction of drug (f) in serum ranging from 0.172 × 10−2to 1.53 × 10−2. There are strong positive correlations between fand kel, fand Vd, and fand the kidney-serum concentration ratio of warfarin. Consistent with theory, there is an excellent positive linear correlation between fand total plasma clearance of the drug. The intersubject variation in fis not related to variations in serum albumin or total protein concentration. There is a strong correlation between values of ffor serum and liver homogenate in individual animals, consistent with the lack of correlation between fin serum and the liver-serum concentration ratio of warfarin. These results show that the pronounced intersubject variation in the elimination of warfarin observed in this investigation was related to interindividual differences in plasma protein binding of the drug. The differences in protein binding cannot be ascribed to differences in plasma protein concentrations and may reflect configurational differences of proteins or the presence of an endogenous displacing agent at different concentrations.