Variable inhibition of human hepatic drug metabolizing enzymes by disulfiram

In healthy adult males, oral treatment with disulfiram exerted variable inhibitory effects on various metabolic parameters of the hepatic microsomal enzyme system: Two 10 mg/kg doses, given at an interval of 24 hr produced only a marginally significant prolongation of the plasma elimination half-life of antipyrine. This effect was not detectable when using as a criterion the formation of 4-OH-antipyrine (aromatic C-hydroxylation), as measured by its renal excretion. In contrast, a single dose of disulfiram (10 mg/kg) was followed by a significant decrease in the formation of D-glucaric acid, which was demonstrable for 6 days and was measured by the renal excretion of D-glucaric acid over 24-hr periods. The same single dose of disulfiram (10 mg/kg) did not affect the activity of the serum gamma-glutamyl transpeptidase. However, a single dose as small as 5 mg/kg caused a temporary but significant reduction in the formation of 4-aminoantipyrine from aminophenazone (oxidative demethylation), where the renal excretion of 4-aminoantipyrine provided a measure of the decrease. During the subsequent phase of excretion, the deficit in 4-aminoantipyrine elimination was completely compensated for. It is concluded from the results that in man the impairment of oxidative N-demethylation constitutes the most sensitive criterion of a measurable inhibitory effect of disulfiram on the hepatic mixed-function oxygenase system.