RT Journal Article SR Electronic T1 Interaction of Several Coumarin Compounds with Human and Canine Plasma Albumin JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 209 OP 218 VO 7 IS 2 A1 ROBERT A. O'REILLY A1 CATHERINE H. MOTLEY YR 1971 UL http://molpharm.aspetjournals.org/content/7/2/209.abstract AB The interactions of several structural analogues of the anticoagulant drug sodium warfarin with human and canine plasma albumins was studied by equilibrium dialysis. The compounds studied were two precursor compounds, coumarin and 4-hydroxycoumarin; the anticoagulant drugs acenocoumarin, bishydroxycoumarin, ethyl biscoumacetate, and phenprocoumon; two metabolic products, 5-hydroxywarfarin and the warfarin alcohols; and the optical enantiomers (-)-S-warfarin and (+)-R-warfarin. The major source of the binding energy for the coumarin compounds was the coumarin nucleus itself. The precursor coumarins, which have almost no anticoagulant activity, showed a single binding site for albumin, while all the coumarin anticoagulant drugs studied showed two binding sites, suggesting that the side chains on the coumarin molecule provided anticoagulant activity not through an increase in binding energy but rather by the formation of a second binding site. There was little difference in the binding energy of the optical enantiomorphs of warfarin. The surprisingly high binding energy of the metabolite 5-hydroxywarfarin probably resulted from the formations of a hydrogen-bonded ring. The binding of warfarin by human plasma albumin was 6 times greater than that by canine plasma albumins. This finding may explain why in man, with greater binding, phenylbutazone potentiates warfarin, but in dogs. with less binding, the enzyme-inducing effects of phenylbutazone predominate. The hydrophobic nature of the substituents on the 4-hydroxycoumarin molecule correlated directly with the binding strength of the compounds to plasma albumin and to the intracellular receptor site for anticoagulant activity.