Complex interaction of rifampin and warfarin.

Rifampin is known to lower plasma warfarin concentrations by increasing the rate of warfarin clearance. We have described a patient in whom an additional potentiating influence on warfarin effect was observed during treatment with rifampin and isoniazid. After cessation of rifampin and isoniazid, prothrombin time was maintained within the same range by a 50% reduction of warfarin doses, despite a twofold rise in the plasma warfarin concentration. This rise in warfarin concentrations can be explained by the known mechanism by which rifampin increases warfarin clearance. After cessation of rifampin, warfarin fractional clearance decreased from 15.2 to 4.2 ml/min; however, the unchanged prothrombin time in the face of the increased warfarin concentration can be explained only by the removal of a potentiating effect that had been present during the coadministration of rifampin and isoniazid. It is likely that rifampin is responsible for this additional potentiating interaction, probably not through a change in warfarin binding, but through a differential effect on warfarin stereoisomer metabolism or through an altered dynamic effect. The role of isoniazid in this interaction cannot be completely ruled out.