Diethyldithiocarbamic acid-methyl ester: a metabolite of disulfiram and its alcohol sensitizing properties in the disulfiram-ethanol reaction.
Diethyldithiocarbamic-acid-methyl ester (DDTC-Me) is a major metabolite of disulfiram. When given to rats, DDTC-Me was found to inhibit the liver mitochondrial low Km aldehyde dehydrogenase (ALDH) without having any effect on the high Km isoenzyme. Inhibition of low Km ALDH by DDTC-Me in vivo exhibited a dose-response relationship, with inhibition of ALDH from 11% to 90% found when DDTC-Me was administered in a dose range from 1.8 to 158 mg/kg, IP. After a single dose of DDTC-Me (41.2 mg/kg, IP), the low Km ALDH was inhibited for 168 hours suggesting an irreversible enzyme inhibition. After an ethanol challenge to DDTC-Me-treated rats, a decrease in mean arterial pressure (MAP) and increase in heart rate was observed. Decreases in MAP occurred almost immediately after ethanol challenge and remained low throughout a four hour post-ethanol period. These results suggest that in vivo administration of DDTC-Me can cause an alcohol-sensitizing reaction, and that DDTC-Me actually may be the metabolite of disulfiram which produces the disulfiram-ethanol reaction. It is proposed the reaction be more correctly identified as the DDTC-Me-Ethanol Reaction or D-MER.
Yourick
J J
JJ
Department of Pharmacology and Toxicology, University of Kansas, Lawrence 66045.
Faiman
M D
MD
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004221:Disulfiram / Q000494:pharmacology*; D004050:Ditiocarb / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D011919:Rats, Inbred Strains
D000431:Ethanol; C016571:methyl diethyldithiocarbamate; D004050:Ditiocarb; D000444:Aldehyde Dehydrogenase; D004221:Disulfiram