In vitro metabolic drug interaction study of warfarin with sildenafil citrate

Abstract

The present study was designed to investigate the in vitro metabolic drug interaction of warfarin and sildenafil in rat and human liver microsomes, and to evaluate the extent to which the in vitro data is predictive of the actual pharmacokinetic interaction between warfarin and sildenafil observed in vivo. Sildenafil inhibits on the hydroxylation of both (S)-and (R)-warfarin, but its inhibitory effect is selective towards (R)-warfarin either in rat or human liver microsomes. With regard to the protein binding, no significant interaction of warfarin and sildenafil in pooled rat serum protein binding was noted. However, based on concentration of warfarin and sildenafil, the either displacement or positive allosteric effect was observed in rat liver microsomal protein binding. Overall findings suggest that the increase in the anticoagulant activity of warfarin in patients taking both warfarin and sildenafil concurrently is attributable in part, if not all, to the changes in warfarin metabolism.