Multiple factors affecting excretion of warfarin in rats.

Dialysis studies showed that the binding of warfarin by rat serum decreased in the presence of either tolbutamide or oxyphenbutazone. A combination of tolbutamide and oxyphenbutazone decreased the binding of warfarin more than either of the drugs separately. The binding of warfarin by serum from fasted rats was less than in controls, presumably from competition between free fatty acids (FFA) and warfarin for the same site(s) on albumin. The binding of warfarin further decreased under the combined effect of fasting and the presence of tolbutamide than under either condition alone. The binding of warfarin was less at 37 degrees C than 23 degrees C and even less at 37 degrees C in the presence of a combination of tolbutamide and oxyphenbutazone. When tolbutamide or oxyphenbutazone was injected 60 min after iv injection of 14C-warfarin there was an increase in the rate of biliary flow, the amount of radioactivity, and its excretion rate in bile. Injecting both drugs at 60 min further increased these variables.