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.