ELIMINATION OF THEOBROMINE METABOLITES IN HEALTHY-ADULTS

The metabolism of theobromine (TB) (500 mg per os) was determined by m easuring plasma and saliva concentrations of TB and its metabolites 0- 24 h after the load, and urinary excretion 0-48 h after the load. TB a nd its six metabolites were separated and quantified by combining high performance liquid chromatography and capillary electrophoresis. The urine analyses showed that unchanged TB accounted for 21+/-4% (mean+/- SD) of total excretion, the remainder being 7-methylxanthine (7-X, 36/-5%), 3-methylxanthine (3-X, 21+/-4%), 6-amino-5 [N-methylformylamino ]-1-methyluracil (6-AMMU, 11+/-4%), 7-methyluric acid (7-U, 10+/-2%), 3,7-dimethyluric acid (3,7-U, 1.3+/-0.6% and 3-methyluric acid (3-U, 0 .5+/-0.4%). In addition to TB, 7-X and 3-X were consistently found in plasma and saliva; 6-AMMU and 7-U were found in plasma and saliva at c oncentrations less than or equal to 2 mu mol l(-1) and 0.2 mu mol l(-1 ), respectively. TB concentrations in plasma and saliva were similar, whereas the saliva concentrations for 7-X and 3-X were found to be 63 +/- 17% of the plasma concentrations for 7-X and 74 +/- 13% for 3-X, r espectively. The high urinary-to-plasma concentration ratio of 7-U (20 0-300) suggests high excretion of 7-U by the kidneys. Excretion of 7-X , 3-X and 6-AMMU was also high (urinary-to-plasma concentration ratio 45-150), whereas the excretion of TB was significantly lower than its metabolites (urinary-to-plasma concentration ratio 4-6). N3-demethylat ion of TB accounted for 58+/-7% of the urinary metabolites, N7-demethy lation for 27+/-6%, C8-oxidation of 7-X for 22+/-4%, C8-oxidation of 3 -X for 2+/-2% and formation of 6-AMMU for 13+/-4%. The ratio of N3- to N7-demethylation of TB remained constant during the load, but the lar ge interindividual variation observed in ratio makes it unsuitable as a function test for evaluation of liver disease.