Serum albumin and the metabolism of disulfiram

The effectiveness of tetraethylthiuram disulfide (DSF) as a drug used in the treatment of alcohol abuse has been limited by the fact that it is degraded rapidly in the tissues and in the serum. Hence, a useful dose-response curve for this drug cannot be determined easily. The degradation in the tissues has been well characterized; however, its fate in the serum is less well understood. Here we kinetically describe the first steps in the degradation of DSF in the serum which results from a covalent interaction of this drug with the free sulfhydryl of serum albumin. DSF and its cleavage product diethyldithiocarbamate (DDC) both absorb significantly in the ultraviolet region. The reduction of DSF with mercaptoethanol to two molecules of DDC resulted in a large change in absorption in this region. The reaction of serum albumin with DSF produced a similar but much slower change in the ultraviolet absorption. As a result of the existence of this slow spectral change, we have been able to directly and continuously monitor the interaction of serum albumin and DSF and have determined that it is an overall first-order process. A model is proposed wherein DSF and serum albumin rapidly form a noncovalent adduct and, subsequently, in a slow unimolecular process, DSF is reduced to one mole of free DDC and one mole of the serum albumin-DDC mixed disulfide. At pH 9 the half-time for this process was 30 to 40 sec, and at pH 7.4 the half-time for this process was 1 to 1.5 min. These results suggest that degradation of DSF by serum albumin is physiologically and clinically important since the drug is maximally active only many hours after administration.