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In Vivo Pharmacodynamic Studies of the Disulfiram Metabolite S ‐Methyl N,N ‐Diethylthiolcarbamate Sulfoxide:Inhibition of Liver Aldehyde Dehydrogenase
Author(s) -
Hart Bruce W.,
Faiman Morris D.
Publication year - 1994
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.1994.tb00023.x
Subject(s) - disulfiram , aldehyde dehydrogenase , in vivo , metabolite , chemistry , pharmacology , pharmacokinetics , in vitro , active metabolite , biochemistry , enzyme , biology , microbiology and biotechnology
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 K m , 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 K m 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 K m , 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. Rats treated with DETC‐MeSO and then challenged with ethanol exhibited an increase in blood acetaldehyde similar to that found from previous studies with disulfiram. In in vitro studies, incubation of rat liver mitochondria with 0.75 μM DETC‐MeSO inhibited rat liver mitochondrial low K m ALDH maximally within 2 hr, whereas purified bovine mitochondrial low K m ALDH was inhibited 90% and 99%, respectively, when incubated for 1 hr with 2 and 6 μM DETC‐MeSO. These studies with rats and purified bovine ALDH show that DETC‐MeSO is a potent inhibitor of mitochondrial low K m ALDH both in vivo and in vitro, providing additional evidence that DETC‐MeSO is the metabolite to which disulfiram must be bioactivated for liver ALDH to be inhibited.