Aging and drug interactions. III. Individual and combined effects of cimetidine and cimetidine and ciprofloxacin on theophylline metabolism in healthy male and female nonsmokers.

The individual and combined effects of cimetidine and ciprofloxacin on theophylline metabolism were examined in healthy young and elderly male and female nonsmokers. Single-dose studies of theophylline pharmacokinetics were performed at base line and on the fifth day of each of three treatment regimens consisting of 400 mg cimetidine every 12 hr, 500 mg ciprofloxacin every 12 hr and the combination of cimetidine and ciprofloxacin. Base-line theophylline plasma clearance and formation clearance of theophylline metabolites decreased with age in both gender groups to a similar extent (20% less in elderly men than in young men; 24% less in elderly women than in young women). Individually, cimetidine and ciprofloxacin produced proportionate declines in plasma theophylline clearance that were similar among the four groups (range, 23.4-32.7% decrease). The combined regimen yielded further impairment in theophylline elimination compared with each agent alone (range, 35.9-42.6% decrease). Cimetidine was a nonselective inhibitor of theophylline metabolic pathways in young men, but it exerted a greater inhibitory effect on N-demethylation pathways in the other groups. Ciprofloxacin inhibited N-demethylations of theophylline to a greater extent than the hydroxylation pathway. Coadministration of these two inhibitors further reduced the formation of theophylline metabolites. The proportionate reduction in formation clearance of theophylline metabolites was similar among the four groups. Thus, the response to inhibition of theophylline metabolism by cimetidine and ciprofloxacin is not influenced by age or gender.