Human disposition and some biochemical aspects of methylxanthines.

The human disposition of caffeine, theophylline, and theobromine is essentially characterized by rapid and complete gastrointestinal absorption; minimal first pass metabolism; distribution throughout the total body water; extensive and, in the case of caffeine almost complete, biotransformation in the liver; and elimination of metabolites from the body via the kidneys. Methylxanthine metabolism is affected by such factors as diet, smoking, pregnancy, use of oral contraceptives, age, and disease state. These factors have been studied extensively in relationship to caffeine disposition, less so for theophylline, and minimally for theobromine as well as the metabolites of these compounds, in particular paraxanthine and the diaminouracils.

Characterization of diaminouracil metabolites of caffeine in human urine.

A major caffeine metabolite (A1) has been isolated from human urine by a combination of solvent extraction, reverse phase high-pressure liquid chromatography, and silica gel open column chromatography. The chromatographic and spectral properties of A1 are identical with an authentic sample of 5-acetylamino-6-amino-3-methyluracil. A stable isotope-labeling study, in which [2-14C]caffeine in a 1:1 mixture of unlabeled caffeine and [1,3-15N-8-13C] caffeine was administered to subjects, demonstrated that the C-8 carbon of caffeine was lost during the biotransformation to A1.

Human metabolism of [1-methyl-14C]- and [2-14C]caffeine after oral administration.

Radiolabeled caffeine was administered orally at 5 mg/kg to adult, male volunteers. Blood, saliva, expired CO2, urine, and feces were collected and analyzed for total radiolabeled equivalents, caffeine, and its metabolites. High-performance liquid chromatography (HPLC) was the principal technique used to separate caffeine and the various metabolites with quantitation by liquid-scintillation counting.