Aging and drug interactions. I. Effect of cimetidine and smoking on the oxidation of theophylline and cortisol in healthy men.

The effect of age on the inhibition of theophylline metabolism was investigated in young and old male cigarette smokers (greater than 20 cigarettes/day) and nonsmokers by stable isotope methodology. Subjects received oral theophylline (510 mg/day) for 14 days and cimetidine (1200 mg/day) during days 1 to 7 or 8 to 14. On days 7 and 14, a tracer dose (10 mg i.v.) of stable isotope-labeled theophylline was administered with the oral dose of theophylline. Plasma clearance in old nonsmokers was 33% less than in young nonsmokers. Values in both young and old smokers were not significantly different but exceeded those in non-smokers. Because volume of distribution was similar in all groups, the half-lives were prolonged in proportion to the decrease in clearance. Although smoking was associated with selective induction of the formation of 3-methylxanthine and 1-methyluric acid, the effect of cimetidine was nonselective and the proportionate inhibitory effects of cimetidine on theophylline metabolism did not differ with age or smoking status. The excretion of 6 beta-hydroxycortisol was similar in smokers and non-smokers but was slightly inhibited by cimetidine. Cimetidine also reduced the interindividual variation in the absorption of theophylline. Despite a reduction in the basal oxidative capacity in healthy male nonsmokers, these results indicate that both the induction of theophylline metabolism by smoking and the inhibition of theophylline metabolism by cimetidine are preserved in old age.