After ingestion, disulfiram (DSF) is rapidly converted, probably in the stomach, to its bis (diethyldithiocarbamato) copper complex. Consequently, absorption and distribution via the gastrointestinal mucosa into the blood might involve both the parent drug and its copper complex. In the blood, both compounds are rapidly degraded to form diethyldithiocarbamic acid (DDC), which is unstable and is further degraded to form diethylamine and carbon disulphide. DDC is also a substrate of phase II metabolism, which involves formation of diethyldithiomethylcarbamate (Me‐DDC) and the glucuronic acid of DDC. Me‐DDC also undergoes oxidative biotransformation to diethylthiomethylcarbamate (Me‐DTC), which is further oxidized to its corresponding sulphoxide and sulphone metabolites. Me‐DTC may to act as a suicide inhibitor with a preference for the mitochondrial low Km isozyme of aldehyde dehydrogenases (ALDH 1), whereas the two S‐oxidized metabolites, especially the sulfone metabolite, are more potent inhibitors not only of ALDH 1, but also of the cytosolic high Km isozyme of ALDH (ALDH 2). The inhibitory reaction between the enzyme and each of the three metabolites is characterized by a covalent adduct formation, probably with the cysteine residue at the active site of the enzymes. The adduct formed is nonreducible at a physiological concentration of glutatione, and inactivation in the presence of this endogenous tripeptide was increased by action in vitro of the sulphoxide and sulphone metabolites. Those findings are all in concordance with the in vivo observations made on DSF. In human volunteers treated with increasing doses of DSF and challenged with ethanol between each of the dosage periods, the mean plasma concentrations of Me‐DTC at steady state were proportional to the DSF doses given. There was also a close relationship between increased oxidative metabolic formation of Me‐DTC, high oxidative formation of acetaldehyde, and the full complements of a valid disulfiram ethanol reaction (DER). Consequently, Me‐DTC in plasma may not only serve as a marker of the oxidative metabolic function of the liver, but also of the therapeutic effectiveness of the treatment in subjects at steady state. Obviously, there is a need for individual dose‐titration regimens. In patients with alcohol‐related severe hepatocellular damage, the oxidative P 450 catalyzed formation of the Me‐DTC and probably also of its sulfoxide and sulphone metabolites is impaired, and thus inactivation of ALDH activity in the liver appears to be delayed or even completely absent. The consequence for the patient may be an insufficient DER. A large variety of solvents, drugs, pesticides and secondary metabolites of mushrooms interact with DSF in different ways. Organic solvents, mushrooms and several drugs sensitize humans to alcohol in a similar way as DSF, but usually with a less pronounced physiological response. However, more important is the metabolic interaction between DSF and drugs which utilize the same metabolic pathways. As a consequence of e...

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Alterations in plasma high density lipoproteins (HDL) were studied in thirty-eight male chronic alcoholics. Twenty-four (63%) of the patients had increased HDL protein (measured immunochemically) and twenty-five (66%) had increased HDL cholesterol (determined after polyanion precipitation of very low density lipoproteins (VLDL) and low density lipoproteins (LDL)). A statistically significant correlation was found between HDL protein and HDL cholesterol (r = 0.39). gamma-Glutamyltransferase (GT) was elevated in eighteen (47%) of the alcoholics. No significant correlations were found between GT and HDL protein or HDL cholesterol. The increase in HDL, as studied by rate zonal ultracentrifugation, was heterogeneous with changes in the HDL2 as well as HDL3 subfractions. It is suggested that determination of HDL total cholesterol, in combination with GT, may represent a valuable and sensitive test for detection of alcoholism.

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The study was designed to elucidate the basic pharmacological and biochemical effects of the disulfiram dose (Antabus) provoking disulfiram-alcohol reaction (DAR) in 52 human volunteers after ethanol challenge. Disulfiram was given daily in increasing doses (1, 100, 200, and 300 mg) in successive 14 day periods, with ethanol challenge at the end of each period, until a DAR was achieved. Irrespective of dose (except the 1 mg dose), the DAR was always accompanied by almost complete inactivation (about 97%) of aldehyde dehydrogenase (ALDH) activity in erythrocytes, plasma concentrations of diethyldithiocarbamic acid methyl ester (Me-DDC) in the range of 8-472 nmol/l and accumulated plasma concentrations of acetaldehyde in the range of 7-197 mumol/l. In four of the volunteers, the cardiovascular effects of the DAR were recorded as a decrease in diastolic blood pressure (14-47 mmHg) and an increase in pulse rate (9-40 beats/min.), accompanied by a two- to fourfold increase in the plasma concentrations of adrenaline and noradrenaline. The enzyme kinetics of ALDH in erythrocytes were regularly analysed in eight volunteers during DSF intake. In addition to the expected decrease in oxidizing capacity, the Km values were also impaired, which suggests that the inhibitor is implicated in an active site directed reaction.