Inhibition of erythrocyte aldehyde dehydrogenase activity and elimination kinetics of diethyldithiocarbamic acid methyl ester and its monothio analogue after administration of single and repeated doses of disulfiram to man

Abstract

The elimination kinetics of the methyl esters of diethyldithiocarbamic acid (Me-DDC) and its monothio analogue (Me-DTC) has been compared in ten alcoholic patients after a single oral dose of 400 mg disulfiram (Antabuse). Erythrocyte aldehyde dehydrogenase (ALDH) activity was continuously followed in the subjects until complete inactivation. The relation between individual steady-state concentrations of Me-DTC in plasma, blood acetaldehyde concentration and the dose of disulfiram sufficient to give the disulfiram alcohol reaction was investigated in 12 healthy volunteers treated with increasing doses of disulfiram and then challenged with ethanol. The mean peak plasma concentration of Me-DDC occurred at 1.8 h and its plasma half-life was 6.3 h. The corresponding values for Me-DTC were 3.3 h and 11.2 h, respectively. This suggests oxidative formation of Me-DTC from Me-DDC. In alcoholics with a rapid decrease in erythrocyte ALDH activity (in less than 5 days), the mean peak plasma concentration of Me-DTC was 278 nmol.l-1, whereas the peak concentration was below the detection limit in subjects with a prolonged inactivation time (7-20 days). The healthy volunteers were divided into three groups of four subjects, with clinically valid disulfiram alcohol reactions at 100, 200, and 300 mg doses of disulfiram, respectively. The mean plasma concentrations of Me-DTC at steady-state were proportional to the disulfiram doses given, compared within groups at different doses, and between groups at equal and different optimal doses of the drug. The concentrations of Me-DTC were significantly increased, as compared above, whereas the blood concentrations of acetaldehyde were not significantly increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma protein binding of disulfiram and its metabolite diethylthiocarbamic acid methyl ester

“…In healthy volunteers taking disulfiram and challenged with ethanol a close relationship was found between the given dose, the plasma concentration of Me-DTC and a valid disulfiram-ethanol reaction (Johansson & Stankiewicz 1989). In alcoholics known to respond to disulfiram medication the mean plasma concentration of Me-DTC agrees with findings in healthy volunteers (Johansson & Stankiewicz 1989). However, in patients who tolerate the medication, i.e.…”

“…However, in patients who tolerate the medication, i.e. those who in spite of the intake of disulfiram could continue drinking alcohol, the plasma concentration of Me-DTC was below the level of detection during treatment (Johansson & Stankiewicz 1989). indicatingan incomplete inhibition ofthe low K , isozyme in these patients.…”

Targeting of Nuclear Factor-κB and Proteasome by Dithiocarbamate Complexes with Metals

“…It seems that the ALDH inhibition by disulfiram is caused by the formation of an intramolecular disulfide bond between the active site thiol and the thiol of another cysteine residue [76][77]. Nevertheless, there are other possible mechanisms of disulfiram inhibitory action on ALDH via its metabolites [78][79][80][81][82][83][84]. Disulfiram is believed to exert its effect after P-450-dependent metabolism [85][86].…”

Depot preparations of disulfiram: experimental and clinical results

“…The sum of the concentrations of diethyldithiocarbamic acid (DDC) and diethyldithiocarbamic methyl ester (Me-DDC) ranged in the alcoholics from 0.48 pM on the first day following implantation to 0.11 pM on day thirty. These concentrations of DS metabolites appear to be high compared to levels measured after much larger oral doses of DS (28).…”