Inhibition of antipyrine elimination by disulfiram and cimetidine: the effect of concomitant administration.

Abstract

We investigated the effect of concomitantly administered disulfiram and cimetidine on antipyrine elimination. On day 1, 2, 4 and 6 of two periods of 6 days one sample antipyrine saliva clearance (APC) was measured in nine healthy volunteers. From day 2 to 6 of period I disulfiram 400 mg dayf1 was administered and on day 5 and 6 cimetidine 1000 mg day-1 was added. In period II only cimetidine was given (on days 5 and 6). On day 4 of period II APC was increased 1.3 fold, probably due to self-induction by repeated antipyrine administration. Taking this into account disulfiram and cimetidine separately decreased APC 0.64 and 0.70 times, respectively. When both inhibitors were given APC was reduced 0.52 times. The results suggest that the effects of cimetidine and disulfiram on antipyrine elimination are additive.Keywords disulfiram cimetidine antipyrine inhibition of drug metabolism

Effect of chronic disulfiram administration on the activities of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and N‐acetyltransferase in healthy human subjects

“…While evidence supports that acute administration of disulfiram results in selective CYP2E1 inhibition, the effect of chronic dosing is unclear. Chronic, long‐term disulfiram administration has been shown to inhibit the metabolism of antipyrine, theophylline, caffeine, phenytoin, and warfarin [8–13], drugs for which CYP2E1 is not the predominant pathway of elimination. These observations suggest that with long‐term administration (> 5 days) the effect of disulfiram becomes nonselective, which would severely limit its use as a diagnostic CYP2E1 inhibitor for cases in which disulfiram must be administered for longer periods of time, such as when evaluating the in vivo role of CYP2E1 in the metabolism of drugs with long elimination half‐lives [14].…”

Diet and cimetidine induce comparable changes in theophylline metabolism in normal subjects

“…Additive or counteractive effects of cimetidine with other factors have been described previously. For example, the effects of concomitant administration of cimetidine and disulfiram, another cytochrome P-450 inhibitor, on antipyrine elimination are additive (20). Moreover, most studies indicate that the effects of cimetidine are not significantly altered by the inducing effects of cigarette smoking on theophylline metabolism (14, 21,22), which indicates that the effects of smoking and cimetidine, or the effects of their cessation, may have additive or counteractive effects on drug metabolism.…”