Cimetidine has been shown to inhibit oxidative metabolism of several drugs while sparing the glucuronidation pathways of drug metabolism. We studied the time-course of inhibition and recovery of cimetidine-inhibited chlordiazepoxide elimination in 7 healthy subjects. Chlordiazepoxide elimination was studied after cimetidine treatment for 1 and 30 days, and after withdrawing cimetidine for 48 h. The plasma clearance of chlordiazepoxide was reduced by 54% (p less than 0.001) after 24 h of cimetidine, by 57% (p less than 0.001) after 30 days of cimetidine and returned to normal after cimetidine was stopped for 48 h. In the absence of changes in volume of distribution, these changes resulted in proportional increases in the elimination half-life (t 1/2 beta) after 24 h and 30 days cimetidine treatment, and returned to pretreatment values after stopping cimetidine. In addition, the impaired chlordiazepoxide elimination was accompanied by inhibition of generation and subsequent elimination of N-desmethylchlordiazepoxide, the first metabolite of chlordiazepoxide metabolism. This study demonstrates a rapid inhibitory effect on chlordiazepoxide elimination, an absence of tolerance to this effect and a rapid reversal of this effect upon stopping cimetidine. These findings may have important therapeutic implications for patients receiving both drugs simultaneously.