Cigarette smoking and theophyiiine clearance and metabolism

Abstract

Differences in plasma theophylline clearance (ClT) and metabolism between smoking and nonsmoking normal subjects were examined by analysis of plasma and urinary theophylline concentrations and of urinary metabolite concentrations under steady-state oral dosing conditions. ClT in smokers (0.053 .+-. 0.006 l/h per kg) was greater than in nonsmokers (0.032 .+-. 0.002 l/h per kg, P < 0.005). Analyses of urinary metabolites revealed that clearance to l-methyluric acid (Cl1MU) and clearance to 3-methylxanthine (Cl3MX) were increased in smokers 1.99- and 2.10-fold over nonsmoking controls (P < 0.005). Clearance to 1.3-dimethyluric acid (ClDMU) was also enhanced in smokers 1.68-fold compared to controls (P < 0.01). The positive relationship between Cl1MU and Cl3MX in smokers and nonsmokers (r = 0.98, P < 0.001) supported the concept that the 2 N-demethylation pathways for theophylline metabolism were under common regulatory control and involved a form of cytochrome P-450 distinct from that mediating 8-hydroxylation of theophylline to DMU. Cigarette smoking induced both cytochrome P-450-mediated pathways of theophylline metabolism but N-demethylation was increased to a greater extent than 8-hydroxylation.