Kinetics of Drug-Drug Interactions in Sheep: Tolbutarnide and Sulfadimethoxine

Abstract

The interaction between sulfadimethoxine and tolbutamide in sheep involving displacement from protein binding sites was investigated quantitatively. A 52% increase in the unbound plasma concentration of tolbutamide was observed in vitro at 37° after the addition of sulfadimethoxine (100μg/ml) to sheep plasma containing toibutamide (50μg/ml). Transient changes in tolbutamide's unbound and total plasma concentrations were noted after acute intravenous administration of sulfadimethoxine to sheep receiving a constant intravenous infusion of tolbutamide. These observations were consistent with displacement of tolbutamide from plasma and tissue binding sites and redistribution of the displaced tolbutamide into body water spaces. The steady state of both agents featured little change in the total plasma tolbutamide concentration, a 150% increase in the unbound plasma tolbutamide concentration, and an inhibition of tolbutamide oxidation by sulfadimethoxine. A model is presented and mathematical relationships are derived that permit a quantitation of the interaction and that indicate that sulfadimethoxine's constant of metabolic inhibition (KI) for tolbutamide metabolism is 65μg/ml.