title: Elimination of theobromine metabolites in healthy adults.
abstract: The metabolism of theobromine (TB) (500 mg per os) was determined by measuring 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 and 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 concentrations < or = 2 mumol l-1 and 0.2 mumol 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, respectively. The high urinary-to-plasma concentration ratio of 7-U (200-300) 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-demethylation of TB accounted for 58 +/- 7% of the urinary metabolites, N7-demethylation 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 large interindividual variation observed in ratio makes it unsuitable as a function test for evaluation of liver disease.
authors.affiliation: Department of Clinical Chemistry, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: N
authors.initials: N
authors.lastname: Rodopoulos
authors.forename: L
authors.initials: L
authors.lastname: Höjvall
authors.forename: A
authors.initials: A
authors.lastname: Norman
mesh_terms: D000328:Adult; D002851:Chromatography, High Pressure Liquid; D019075:Electrophoresis, Capillary; D005260:Female; D006801:Humans; D008297:Male; D012016:Reference Values; D012463:Saliva / Q000378:metabolism; D013805:Theobromine / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
chemical_list: D013805:Theobromine