Dose‐Effect Relationship of Disulfiram in Human Volunteers. II: A Study of the Relation between the Disulfiram‐Alcohol Reaction and Plasma Concentrations of Acetaldehyde, Diethyldithiocarbamic Acid Methyl Ester, and Erythrocyte Aldehyde Dehydrogenase Activity

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Abstract
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 μmol/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 Kmvalues were also impaired, which suggests that the inhibitor is implicated in an active site directed reaction.