Theophylline and caffeine metabolism in man

Because only 4 % of human urinary caffeine metabolites are trimethyl derivatives, in contrast to 42 % in the rat, demethylation of caffeine into dimethylxanthines and the metabolic pathways of these dimethylxanthines were studied in man. After oral administration of caffeine to overnight fasted volunteers, plasma kinetics of caffeine and paraxanthine, theophylline, theobromine produced by demethylation were analyzed and showed a parallel increase of caffeine and paraxanthine while theophylline and theobromine plasma concentration exhibited a small increase. Quantitative metabolic study of dimethylxanthines demonstrated that paraxanthine is the most important pathway in man and its high plasma concentration cannot be explained by a lower level of metabolism or urinary excretion compared with theobromine and theophylline. Uracil derivatives of caffeine, paraxanthine and theobromine were identified and quantified with 14 other metabolites. In addition 5-acetylamino-6-amino-3-methyluracil was also quantified after paraxanthine administration. 1-Methylxanthine was shown to be the precursor of this acetylated uracil. Quantitatively the paraxanthine pathway corresponds to 72% of the first demethylation of caffeine and half of the urinary metabolites are 1-methylxanthine and 1-methylxanthine derivatives.