Interaction of the anticoagulant drug warfarin and its metabolites with human plasma albumin.
The interaction of the anticoagulant drug warfarin and its metabolites with human plasma albumin was studied by equilibrium dialysis. A 20-fold variation of buffer ionic strength (0.017-0.340) caused no significant change in the warfarin association constant. But the binding strength rose significantly as the pH was increased from 6.0 to 9.0 and then declined at pH 10.0. The 6-, 7-, and 8-hydroxywarfarin metabolites showed a 7- to 23-fold reduction in binding strength at pH 10.0. These data indicate that the molecular basis of the interaction is nonelectrostatic and that the introduction of polar hydroxyl groups on the coumarin nucleus by metabolism reduces its hydrophobic binding surface. The interaction was markedly exothermic and showed a positive entropy (increased molecular disorder), which suggests cooperative hydrogen and hydrophobic bonding as the molecular basis for the binding of warfarin to albumin. The marked albumin binding and nonpolar character of warfarin explains the respective absence and presence of the unchanged drug in urine and plasma of warfarintreated patients, while the more polar character and lesser albumin binding of the metabolites probably determines their absence in plasma and presence in urine. The relatively marked binding to albumin of the 4'-hydroxywarfarin metabolite suggests that it may occur in the plasma of warfarin-treated patients. The data suggest that a direct correlation exists between the interaction of warfarin with plasma albumin and the interaction with the warfarin receptor site.
D001665:Binding Sites; D002247:Carbon Isotopes; D003956:Dialysis; D006801:Humans; D011485:Protein Binding; D012709:Serum Albumin; D014859:Warfarin / Q000097:blood*
D002247:Carbon Isotopes; D012709:Serum Albumin; D014859:Warfarin