Competition between serum albumin and soluble fraction of liver for binding of warfarin and other drugs

Abstract

The binding of Warfarin by human serum albumin (HSA) and subcellular fractions from rat liver was investigated to evaluate the roles of such interactions in the pharmacokinetic properties of the anticoagulant. In vitro intracellular distribution studies showed that Warfarin was bound primarily by the soluble fraction of rat liver. Equilibrium dialysis studies were carried out to test the hypothesis that the hepatic extraction of Warfarin and drug interactions between Warfarin and other drugs involved competition between albumin and the soluble fraction of liver. A three compartment dialysis cell was designed and constructed for such studies. Three types of competitive binding interactions were identified. Iopanoic acid displaced Warfarin from HSA resulting in increased Warfarin in the protein-free compartment and in the compartment containing the soluble fraction. On the other hand, tolbutamide displaced Warfarin from HSA to the liver soluble fraction with relatively little effect on unbound anticoagulant. Sulfinpyrazone produced a third type of interaction characterized by displacement of Warfarin from HSA with an increase in the concentration of unbound drug. It was concluded that competitive binding between albumin and soluble liver proteins, is important in the hepatic uptake of Warfarin. The three compartment dialysis cells may be useful to simulate the distribution of drugs and drug combinations between non-dialyzable macromolecules.