DISULFIRAM IMPAIRMENT OF DRUG METABOLISM BY RAT LIVER MICROSOMES

Abstract

In order to study the effect of in vivo pretreatment with disulfiram (tetraethylthiuram disulfide, Antabuse) on hexobarbital sleeping time and the in vitro metabolism of drugs by rat liver microsomes, rats were treated i. p. (200 mg/ kg) or p. o. (1-2 g/ kg) with disulfiram and killed at various time intervals. Although a 3-fold increase in hexobarbital aleeping time was observed after two-hour pretreatment (i.p.), no inhibition of hexobarbital metabolism by 9000 X g liver supernatant was seen. An impairing effect on drug metabolism, as measured by microsomal ethylmorphine N-demethylaae activity, appeared at eight hours after i.p. injection. The impairment lasted at least 72 hours but was not detectable after seven days. Associated with the decrease in N-demethylase activity were decreases in cytochrome P450 content and reduced nicotinamide-adenine dinucleotide phosphate (NADPH) cytochrome c reductase and cytochrome P450 reductase activities. The decrease of the cytochrome P450 reductase more closely paralleled the effect observed on N-demethylation of ethylmorphine than did the other parameters. The metabolite of disulfiram, diethyldithiocarbamate, in the same dosage had very little effect on N-demethylase activity and no significant effect on cytochrome P-450 and NADPH cytochrome P-450 reductaae activity.