AGING AND DRUG-INTERACTIONS .3. INDIVIDUAL AND COMBINED EFFECTS OF 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 ma le and female nonsmokers. Single-dose studies of theophylline pharmaco kinetics were performed at base line and on the fifth day of each of t hree treatment regimens consisting of 400 mg cimetidine every 12 hr, 5 00 mg ciprofloxacin every 12 hr and the combination of cimetidine and ciprofloxacin. Base-line theophylline plasma clearance and formation c learance 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, cimeti dine and ciprofloxacin produced proportionate declines in plasma theop hylline clearance that were similar among the four groups (range, 23.4 -32.7% decrease). The combined regimen yielded further impairment in t heophylline 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 th e hydroxylation pathway. Coadministration of these two inhibitors furt her reduced the formation of theophylline metabolites. The proportiona te reduction in formation clearance of theophylline metabolites was si milar among the four groups. Thus, the response to inhibition of theop hylline metabolism by cimetidine and ciprofloxacin is not influenced b y age or gender.