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 · hr-1 · kg-1) was greater than in nonsmokers (0.032 ± 0.002 l · hr-1 · kg-1, 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 fold and 2.10-fold over nonsmoking controls (P < 0.005). Clearance to 1.3-dimethylurie acid (ClDMU) was also enhanced in smokers 1.68-fold compared to controls (P < 0.01). The positive relationship between Cl1MU and Cl3MX in both smokers and nonsmokers (r = 0.98, P < 0.001) supports the concept that the two N-demethylation pathways for theophylline metabolism are under common regulatory control and involve a form of cytochrome P450 distinct from that mediating 8-hydroxylation of theophylline to DMU. These results suggest that cigarette smoking induces both of the cytochrome P450-mediated pathways of theophylline metabolism but that N-demethylation may be increased to a greater extent than 8-hydroxylation.