Alterations in the D-glucuronic Acid Pathway and Drug Metabolism W Exogenous Compounds

Treatment of guinea-pigs with disulfiram for 8 days resulted in a significant enhancement of the in vitro activities of the N-demethylation of aminopyrine and the glucuronyl conjugation of p-mtrophenol. This increase was accompanied by an induction of liver growth and an increase in microsomal protein content. It might be concluded that disulfiram has inductive properties with respect to drug metabolism. Disulfiram pretreatment also resulted in an enhanced urinary Dglucaric acid excretion, approaching 200 per cent of the controls at the 7th day of treatment. In contrast a decrease in the excretion of D-glucaric acid was observed in the 16-24 hr period after the beginning of the treatment. The same was found after loading the animals with exogenous D-glucuronolactone. These effects could be explained in terms of an inhibition of D-glucuronolactone dehydrogenase due to competition between disulfiram and the cosubstrate NAD+. Observations indicate that disulfiram pretreatment may exert a biphasic effect, an acute inhibitory activity and an induction of drug metabolism.