Comparative aspects of disulfiram and its metabolites in the disulfiram-ethanol reaction in the rat.
Diethyldithiocarbamate-methyl ester (DDTC-Me), a metabolite of disulfiram, has been shown recently to produce a disulfiram-ethanol reaction (DER). Studies were carried out to compare the ethanol-sensitizing properties of DDTC-Me with those of disulfiram and diethyldithiocarbamate (DDTC) in the rat. All three drugs inhibited liver mitochondrial low Km aldehyde dehydrogenase (ALDH) in vivo, with maximal ALDH inhibition occurring 8 hr after drug administration. The onset of ALDH inhibition was most rapid after DDTC-Me administration. ALDH was inhibited approximately 50% 0.5 hr after DDTC-Me, whereas ALDH was inhibited only 5 and 10%, respectively, after disulfiram and DDTC. Not until 8 hr after drug treatment was ALDH inhibition the same for disulfiram, DDTC and DDTC-Me. The degree of ALDH inhibition from 8 to 172 hr after dosing was the same for all three drugs. An ethanol (1 g/kg, 20% v/v) challenge administered to rats treated with disulfiram (75 mg/kg), DDTC (114 mg/kg), or DDTC-Me (41.2 mg/kg) for 8 hr produced similar blood acetaldehyde/ethanol concentration-time profiles. In addition, all three agents produced a DER (hypotension, tachycardia). No DER occurred if ethanol was administered more than 24 hr after drug pretreatment. The hypotension associated with the DER correlated with the increased blood acetaldehyde but not blood ethanol. A threshold blood acetaldehyde of 110 microM appeared to be required for hypotension to occur, and this was related to ALDH inhibition of approximately 40%. The tachycardia associated with the DER correlated more with blood ethanol. After DDTC-Me administration, no disulfiram or DDTC could be detected in the plasma. Furthermore, no DDTC-Me was found in the plasma 8 hr after DDTC-Me administration, suggesting that no correlation exists between the DER and plasma concentration of DDTC-Me and most likely disulfiram. These data suggest that the alcohol-sensitizing properties of DDTC-Me are similar to those observed with disulfiram and DDTC. Since DDTC-Me is an active metabolite and more potent than disulfiram and DDTC in producing a DER, disulfiram metabolism is an important consideration in the disulfiram-ethanol reaction.
Yourick
J J
JJ
Department of Pharmacology and Toxicology, University of Kansas, Lawrence 66045.
Faiman
M D
MD
D000079:Acetaldehyde / Q000097:blood; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004221:Disulfiram / Q000378:metabolism / Q000494:pharmacology*; D004050:Ditiocarb / Q000031:analogs & derivatives* / Q000494:pharmacology; D000431:Ethanol / Q000097:blood*; D005260:Female; D051381:Rats; D011919:Rats, Inbred Strains
D000431:Ethanol; C016571:methyl diethyldithiocarbamate; D004050:Ditiocarb; D000444:Aldehyde Dehydrogenase; D000079:Acetaldehyde; D004221:Disulfiram