Metabolic disposition of the methylxanthines in man

Theophylline and theobromine metabolism in man was studied after single dose intravenous administration (theophylline) and at steady-state during chronic oral administration (theophylline and theobromine). Co-administration of the xanthine oxidase inhibitor allopurinol with theophylline caused a decreased excretion of 1-methyluric acid (1MU) and an increased excretion of 1-methylxanthine (1MX). In the case of theobromine, allopurinol caused the disappearance of 7-methyluric acid (7MU) from urine and an increase in excretion of 7-methylxanthine. It is concluded that 1MU and 7MU arise by initial demethylations of theophylline and theobromine respectively, followed by xanthine oxidase mediated 8-oxidation of the monomethylxanthine. Other pathways for metabolism of the dimethylxanthines were not affected by allopurinol and are assumed to be cytochrome P-450 mediated. In children, theophylline total clearance was enhanced and all metabolic pathways were increased to approximately the same extent. In premature neonates, oxidative metabolism of theophylline was absent but 7-methylation to caffeine accounted for about 2 % of the dose. In cigarette smokers the demethylation pathways for theophylline were increased to a greater extent than 8-oxidation to 1,3-dimethyluric acid (DMU). Cimetidine inhibited the demethylation pathways but had little effect on the clearance to DMU. Inhibition of demethylation was more marked in cigarette smokers. These results, together with the high degree of correlation observed between clearance to 1MU and clearance to 3MX, suggests that the two demethylation reactions are under a common regulatory control which is distinct from that for the 8-oxidation to DMU.