Elimination of caffeine metabolites in man

Plasma, saliva and urinary caffeine (CA), paraxanthine (PX), theobromine (TB), theophylline (TP) and their metabolites were, after separation into fractions by reversed-phase high-performance liquid chromatography (HPLC), quantitated by capillary electrophoresis (CE). In healthy adults, 96% of the total amount of excreted compounds derived from CA were dimethylxanthines (DMXs) and metabolites, the remainder 4% being nonmetabolized CA and its non-demethylated urate. The PX pathway accounted for 78% of the excreted DMXs and metabolites, with the TB pathway accounting for 14% and TP pathway for 8%, 24 h after CA ingestion. The percent of the area under the curve (AUC) for PX was lower than the percent excreted metabolites corresponding to the PX pathway, whereas the AUC for TB was higher than the TB pathway value and the percent of AUC for TP was similar to the TP pathway value. The high urinary-to-plasma concentration ratios of 7-U after TB ingestion, and 1,3-U and 1-U after TP ingestion, suggest their high excretion by the kidneys. The reactions involved in metabolism of DMXs remained constant during the load, suggesting that N-demethylations and C8-oxidations of DMXs occur simultaneously and not sequentially. The distribution of urinary metabolites suggests large differences in excretion of 1-X, 1-U and 1,3-U depending on whether the metabolites are formed after CA ingestion or after ingestion of PX and TP, respectively. The intestinal absorption of monomethylxanthines (MMXs) is high and rapid, whereas the absorption of monomethylurates (MMUs) is low and slow as judged from urinary excretion of metabolites and unchanged compounds. Prior to excretion all of 1-X and approximately 25% of 7-X were oxidized to the corresponding urates, whereas essentially all of 3-X was excreted as non-metabolized compound. The distribution of urinary metabolites suggests large differences in excretion of 1-X and 1-U depending on whether the metabolites are formed after ingestion of MMXs or after ingestion of CA and DMXs. In liver cirrhosis the metabolism through the PX pathway was decreased, whereas the metabolism through the TB + TP pathways was increased. In liver cirrhosis the total N3- and N7-demethylations were decreased, whereas total N1-demethylations were increased. The major C8-oxidation reaction, oxidation of 1-methylxanthine, was increased in liver cirrhosis.