Inhibitory mechanism of sulfaphenazole on tolbutamide elimination from plasma in rat.

Abstract

Sulfaphenazole[SP; N1-(1-phenylpyrazol-5-yl)sulfanilamide] potentiates the hypoglycemic activity of tolbutamide [TB; 1-butyl-3-p-tolylsulfonylurea] by increasing its half-life in plasma. The inhibitory mechanisms of SP on tolbutamide TB elimination from plasma in the rat were examined. Three mechanisms were proposed: inhibition of distribution of TB in the liver, inhibition of urinary excretion of TB and inhibition of liver oxidation of TB. Only the 3rd mechanism was evidenced. The reason SP, which is not oxidized in vivo, inhibits the oxidation of TB was explained by the finding that SP binds to hepatic cytochrome P-450. SP, showing type II P-450-substrate difference spectrum, gives a stronger binding tendency than other sulfa drugs, such as sulfadimethoxine, sulfisoxazole and sulfamethoxazole, which have been reported to have little effect on TB elimination. A compound not oxidized in vivo could possibly have an effect on oxidative drug metabolism, and a spectrum study of P-450-substrate complex is a useful tool to predict such an effect, i.e., drug-drug interaction in vivo.