In vivo pharmacodynamic studies of the disulfiram metabolite S-methyl N,N-diethylthiolcarbamate sulfoxide: inhibition of liver aldehyde dehydrogenase.
S-methyl N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO) is proposed to be the metabolite of disulfiram responsible for the in vivo inhibition of liver low Km aldehyde dehydrogenase (ALDH) in the rat. Studies were conducted in male Sprague-Dawley rats and also in vitro using both rat liver mitochondrial and purified bovine mitochondrial low Km ALDH to investigate further the pharmacodynamic and pharmacokinetic characteristics of DETC-MeSO. Administration of DETC-MeSO to rats produced a rapid and maximal inhibition of liver mitochondrial low Km ALDH within 2 hr, which was still inhibited 30% after 168 hr. After DETC-MeSO treatment, the maximum plasma concentration of DETC-MeSO was reached within 0.5 hr, with DETC-MeSO being undetectable 2 hr after DETC-MeSO dosing. Although a trace amount of DETC-Me was detected in the plasma 0.5 hr after DETC-MeSO administration to rats, this disappeared within 1 hr. When rats were treated with disulfiram, the maximal plasma concentration of DETC-MeSO was found within 2 hr, with only a very small quantity of DETC-MeSO still detectable after 8 hr. Rats also were given the disulfiram metabolites diethyldithiocarbamate (DDTC), diethyldithiocarbamate-methyl ester (DDTC-Me), and S-methyl N,N-diethylthiolcarbamate (DETC-Me), and plasma analyzed for DETC-MeSO 2 hr after the administration of these metabolites. DETC-MeSO was detected in plasma, further illustrating that DETC-MeSO can be found in plasma after the administration of either disulfiram, or the subsequent in vivo metabolites DDTC, DDTC-Me, or DETC-Me.(ABSTRACT TRUNCATED AT 250 WORDS)
Hart
B W
BW
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; D002417:Cattle; D046508:Culture Techniques; D004221:Disulfiram / Q000493:pharmacokinetics*; D004050:Ditiocarb / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000201:enzymology*; D008297:Male; D008930:Mitochondria, Liver / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley
C073220:S-methyl N,N-diethylthiolcarbamate sulfoxide; C016571:methyl diethyldithiocarbamate; D004050:Ditiocarb; D000444:Aldehyde Dehydrogenase; D000079:Acetaldehyde; D004221:Disulfiram