COMPARATIVE PHARMACOKINETICS OF COUMARIN ANTICOAGULANTS .6. EFFECT OF PLASMA PROTEIN BINDING ON DISTRIBUTION AND ELIMINATION OF BISHYDROXYCOUMARIN BY RATS

The partitioning of bishydroxycoumarin (BHC) from rat plasma to an organic solvent phase decreases with increasing drug concentration to a minimum value and then increases as the concentration is further increased. The same type of profile is observed in the partitioning of BHC from rat plasma to the liver, both in vitro and in vivo. The elimination of large doses (60 mg./kg.) of BHC in the rat is much more rapid than the elimination of smaller (2‐20 mg./kg.) doses. A plot of the elimination rate constant of BHC as a function of dose yields a curve which is similar to the partitioning profiles of BHC from plasma to liver and from plasma to organic solvent. The minimum concentration ratio, liver:plasma, in a perfused liver system and in intact animals, and the minimum in vivo elimination rate constant, occur at the same plasma concentration of BHC. These results reflect the unusual concentration dependence of the plasma protein binding of this drug. They demonstrate the pronounced effect of protein binding on the distribution of BHC, and the effect of distribution on the elimination of this drug. Copyright © 1969 Wiley‐Liss, Inc., A Wiley Company