Ticrynafen-racemic warfarin interaction: hepatotoxic or stereoselective?

To examine the ticrynafen-warfarin interaction, normal subjects received large single doses of 1.5 mg/kg racemic warfarin with and without daily oral doses of 250 mg ticrynafen beginning 3 days before warfarin and continuing for the duration of hypoprothrombinemia. Daily blood samples were analyzed for one-stage prothrombin time (Quick method) and warfarin concentrations (high-pressure liquid chromatography). Ticrynafen induced augmentations of both prothrombin time and warfarin concentration (P less than 0.001). The interaction was evaluated further with separated warfarin enantiomorphs. Ticrynafen induced augmentation of prothrombin times and warfarin concentrations of S-warfarin, but had little effect on R-warfarin. Thus, ticrynafen probably augments the hypoprothrombinemia of racemic warfarin by reducing metabolic clearance of S-warfarin. The lack of effect of ticrynafen on R-warfarin suggest that the interaction is stereoselective rather than hepatotoxic.