Cigarette smoking and theophylline clearance and metabolism

Differences in plasma theophylline clearance (Cl_T) 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. Cl_T 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 (Cl_1MU) and clearance to 3-methylxanthine (Cl_3MX) were increased in smokers 1.99 fold and 2.10-fold over nonsmoking controls (P < 0.005). Clearance to 1.3-dimethylurie acid (Cl_DMU) was also enhanced in smokers 1.68-fold compared to controls (P < 0.01). The positive relationship between Cl_1MU and Cl_3MX 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.