Pharmacological effects of diethylthiocarbamic acid methyl ester, the active metabolite of disulfiram?
A recently discovered metabolite, diethylthiocarbamic acid methyl ester (Me-DTC), has been found in the plasma of man and rats in much higher concentrations than any other described metabolite after therapeutic doses of disulfiram. Me-DTC, in contrast to other disulfiram metabolites, is a potent inhibitor of liver aldehyde dehydrogenase (ALDH) in vitro. Like disulfiram, Me-DTC had a pronounced hypothermic effect in rats. This hypothermic effect and the augmented blood pressure response to ethanol challenge in rats developed rapidly with Me-DTC but were somewhat delayed with disulfiram. The blood pressure response outlasted the presence of Me-DTC in plasma (less than 24 h); a significant effect was found 48 h after pretreatment but not 72 h after a single dose. No effect was observed when ethanol was given 15 min before Me-DTC or disulfiram. These latter two observations are consistent with a function of Me-DTC as a suicide inhibitor of ALDH. Since Me-DTC has been reported to inhibit ALDH in vitro, even under anaerobic conditions, Me-DTC may be the active metabolite of disulfiram.
Petersen
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EN
Department of Pharmacology, A/S Dumex, Copenhagen S, Denmark.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D004221:Disulfiram / Q000378:metabolism* / Q000494:pharmacology; D004050:Ditiocarb / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D051381:Rats; D011919:Rats, Inbred Strains; D013859:Thiocarbamates / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity
D013859:Thiocarbamates; D000431:Ethanol; C016571:methyl diethyldithiocarbamate; D004050:Ditiocarb; D004221:Disulfiram