CIGARETTE-SMOKING AND THEOPHYLLINE METABOLISM - EFFECTS OF CIMETIDINE

The inhibition of theophylline metabolism by cimetidine was investigated in young male cigarette smokers (> 20 cigarettes/day) and nonsmokers by stable isotope methodology. Subjects received oral theophylline (510 mg/day) for 14 days and cimetidine (1200 mg/day) over days 1-7 or 8-14. On days 7 and 14, a tracer dose (10 mg) of stable isotope-labeled theophylline was injected i.v. with the oral dose of theophyline. Serial plasma samples were then obtained for 24 h and both molecular forms of theophylline were assayed by mass spectrometry after purification by HPLC [high performance liquid chromatography]. Theophylline bioavailability, volume of distribution, and protein binding were of the same order in both groups and were not affected by cimetidine. Although the basal theophylline elimination rate constant was 46% greater and clearance was 54% greater in smokers than in nonsmokers, the proportionate changes in steady-state plasma concentrations, t1/2 [half-time], and clearance due to cimetidine were much the same in both groups. Plasma thiocyanate concentrations were higher in smokers than in nonsmokers and were related to theophylline clearance. Cimetidine apparently inhibits theophylline metabolites to a similar extent in both smokers and nonsmokers. Determination of plasma thiocyanate levels may be valuable in the prediction of theophylline clearance.