The effect of erythromycin on the disposition kinetics of warfarin

Erythromycin is generally regarded as innocuous in regard to adverse interactions with other drugs. Recently, however, its potentiation of theophylline and warfarin has been reported. The present investigation defined more specifically the kinetics of the interaction between erythromycin and warfarin. Warfarin kinetics were evaluated in 12 normal subjects who took a single 1 mg/kg dose of warfarin with and without erythromycin. Erythromycin (250 mg p.o.) every 6 h for 8 days decreased warfarin clearance by 14% (p less than 0.001). Warfarin's apparent volume of distribution was not affected. Further, the effect of erythromycin was greatest among subjects whose control phase warfarin clearance was relatively slow, and least among those whose control phase warfarin clearance was relatively fast. The magnitude of the decrease in warfarin clearance correlated negatively with control warfarin clearance (r = -0.89, p less than 0.005). These data are consistent with the interpretation that erythromycin can potentiate warfarin-induced hypoprothrombinemia by slowing warfarin clearance.