Dose-dependent inhibition of theophylline metabolism by disulfiram in recovering alcoholics

Abstract

The influence of disulfiram on theophylline metabolism was studied in 20 recovering alcoholics. Ten of the patients, who were selected at random, received 250 mg of disulfiram daily. The other 10 patients received 500 mg of disulfiram daily. Two single-dose studies of theophylline kinetics were performed--one as a baseline control and the other after 1 week of treatment with disulfiram. With disulfiram pretreatment, the plasma clearance of theophylline was decreased from 105.7 +/- 10.2 (mean +/- SEM) to 83.1 +/- 8.1 ml/kg per hour (p less than 0.001) in the 250 mg group and from 94.3 +/- 13.3 to 65.4 +/- 10.7 ml/mg per hour (p less than 0.001) in the 500 mg group. The elimination half-life was prolonged significantly in both groups. The percent reduction in theophylline clearance was greater in the 500 mg group (32.5 +/- 3.1; range, 21.6 to 49.6) than it was in the 250 mg group (21.2 +/- 1.7; range, 14.6 to 29.6; p less than 0.01). Disulfiram decreased the formation of all theophylline metabolites in smokers in both treatment groups. In each group, the hydroxylation pathway was affected more than the demethylation pathway. These data indicate that at therapeutic doses disulfiram exerts a dose-dependent inhibitory effect on theophylline metabolism. Depending on the dose of disulfiram, a dose reduction of theophylline by as much as 50% may be necessary to minimize the risk of toxicity.