INHIBITORY MECHANISM OF SULFAPHENAZOLE ON TOLBUTAMIDE ELIMINATION FROM PLASMA IN RAT

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The inhibitory mechanisms of sulfaphenazole (SP) on tolbutamide (TB) elimination from plasma in the rat were examined. Three mechanisms, 1) inhibition of distribution of TB in the metabolic organ, the liver, 2) inhibition of excretion of TB in the urine and 3) inhibition of oxidation of TB in the liver were proposed. Only the third mechanism, of which SP inhibits the microsomal oxidation of TB was evidenced. The reason why 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 the type II of P-450-substrate difference spectrum, gives a much stronger binding tendency than other sulfa drugs, such as sulfadimethoxine, sulfisoxazole and sulfamethoxazole, which have been reported to have little effect on TB elimination. It is suggested that a compound, not oxidized in vivo, can possibly have an effect on oxidative drug metabolism, and that a spectrum study of P-450-substrate complex is a useful tool to predict such an effect, i.e., drug-drug interaction in vivo.
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