Individual and combined effects of cimetidine and ciprofloxacin on theophylline metabolism in male nonsmokers.

1. The individual and combined effects of cimetidine and ciprofloxacin on theophylline metabolism were examined in six young male nonsmokers. 2. Treatment sequence consisted of 7 days each of cimetidine 400 mg p.o. every 12 h. ciprofloxacin 500 mg p.o. every 12 h, and the combination of cimetidine and ciprofloxacin. 3. Studies of theophylline pharmacokinetics were performed at baseline and on the fifth day of each regimen. 4. Individually, cimetidine and ciprofloxacin decreased the clearance of theophylline by 25% and 32%, respectively. Therapy with the combined regimen resulted in a 41% reduction in theophylline clearance, which was greater than that achieved with each drug alone (P < 0.01). 5. Ciprofloxacin, in contrast to cimetidine, inhibited N-demethylations of theophylline to a significantly greater extent than the hydroxylation pathway. Combined treatment produced a further decline in formation of 1,3-dimethyluric acid than each drug alone. 6. These data suggest that coadministration of cimetidine and ciprofloxacin exerts a greater impairment of theophylline biotransformation than each inhibitor alone. The enhanced inhibitory effect from the two inhibitors will occur only when sub-maximal doses of each individual agent are used.