The Effect of Cyclodextrin Inclusion Complexation on the in Vitro Protein Binding and in Vivo Prothrombin Time of Warfarin

Abstract

That the inclusion complexation occurred in an aqueous solution was proved by solubility determination and a membrane permeation study. The effects of inclusion complexation on the protein binding and prothrombin time of warfarin were studied by the technique of ultrafiltration and prothrombin time measurements respectively. The apparent stability constant of 1:l complex was obtained from the initial portion of the straight line of phase solubility diagrams. The apparent stability constant of α or β - cyclodextrin complex is 10.29 M ^-1 or 148.88 M^-1. The greater the stability constant of the inclusion complex the less the permeability of the warfarin. The magnitude of the stability constant of the inclusion complex also determined the protein binding and the prothrombin time of warfarin. The greater the stability constant of the inclusion complex, the lesser the protein binding and the more prolonged the prothrombin time of warfarin. β-cyclodextrin showed a significantly different behavior from α-cyclodextrin in vitro protein binding and in vivo prothrombin time. The present results indicate a greater stability constant of the inclusion complex formed might determine the binding of warfarin to ablbumin and lead to an increased anticoagulant activity of warfarin.