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.

The effect of 5 days of oral tocainide (400 mg every 8 h) on the kinetics of theophylline given as a single 5 mg kg-1 i.v. infusion over 30 min was investigated in eight healthy male nonsmokers. Treatment with tocainide decreased the plasma clearance of theophylline from 37.5 ± 6.9 (mean ± s.d.) to 33.7 ± 5.0 ml kg-' h-1 (difference -3.8, 95% CI, -1.7 to -5.9; P = 0.004) and increased its terminal elimination half-life from 9.7 ± 2.5 to 10.4 ± 2.1 h (difference 0.7, 95% CI, 0.2 to 1.2; P = 0.011). Tocainide decreased the formation clearances of 3-methylxanthine and 1-methyluric acid, but the formation clearance of 1 ,3-dimethyluric acid was unaltered. These data indicate that tocainide exerts a modest inhibitory effect on theophylline metabolism. The magnitude of this change is substantially smaller than that reported to be produced by mexiletine.