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.

Metabolism of theophylline by cDNA‐expressed human cytochromes P‐450.

“…Cimetidine [26], mexiletine [27], propranolol [28] and ciprofloxacin [29] inhibit the demethylation of theophylline to a greater extent than its hydroxylation, and the converse is true for disulfiram [30]. The differential effects on theophylline pathways may be explained.…”

“…The differential effects on theophylline pathways may be explained. If CYP2E1 contributes to hydroxylation of theophylline as a low-affinity high-capacity enzyme in vivo the 30% decrease in theophylline clearance observed by Loi et al [30] in the presence of disulfiram is understandable. This hypothesis is supported by our in vitro data, since the contribution of CYP2E1 to DMU formation is predicted to begin to increase in the therapeutic range of plasma concentrations (5 and 20 jg ml-or 0.03-0.11 mM) [31].…”

Influence of Endogenous and Exogenous Effectors on the Pharmacokinetics of Theophylline

“…(185) Similar values have been described for disulfiram (21 to 31%). [198] The antidepressant viloxazine inhibited the metabolism of theophylline by 28%)242] The thrombolytic agent ticlopidine reduced clearance by 37%, [216] while the antiarrhythmics mexiletine and tocainide also reduced the clearance of theophylline.l208-211 ,217] Not only drugs , but also other substances like the alkaloid component of black pepper, piperidine, can decrease theophylline elimination)213]…”

Pharmacotherapy of Alcohol Use Disorders

“…Concomitant disulfiram and warfarin therapy has resulted in a potentiation of warfarin's hypoprothrombinemic effect (O'Reilly, 1981). Disulfiram also inhibits the metabolism of theophylline (Loi et al, 1989;Upton, 1991).…”