Elimination of theophylline metabolites in healthy adults

The metabolism of theophylline (TP) (540 mg per os) was determined by measuring plasma and saliva concentrations of TP and its metabolites, 0-24 h after loading, and urinary excretion 0-48 h after loading. TP and its five metabolites were separated and quantified by combining high-performance liquid chromatography and capillary electrophoresis. In addition to TP, 1,3-U, 3-X and 1-U were consistently found in plasma and saliva. The area under the plasma concentration-time curve (AUC) showed that TP accounted for 91 +/- 4% (mean +/- SD) of the total AUC in plasma with 1,3-U accounting for 3.1 +/- 1.4%, 3-X for 3.4 +/- 1.8% and 1-U for 2.5 +/- 1.5%. The urine analyses showed that unchanged TP accounted for 19 +/- 5% of total excretion, the remainder being 1, 3-dimethyluric acid (1,3-U, 41 +/- 6%), 1-methylxanthine (1-X, 2 +/- 0.8%), 1-methyluric acid (1-U, 26 +/- 6%), 3-methylxanthine (3-X, 11 +/- 3%) and 3-methyluric acid (3-U, 1 +/- 0.3%). Highest excretion rates were observed for 1,3-U (70 +/- 29 mumol/h), 1-U (40 +/- 26 mumol/h) and 3-X (20 +/- 15 mumol/h) 6-9 h after TP ingestion suggesting the high excretion of 1,3-U, 1-U and 3-X by the kidneys. The highest excretion rate of TP (50 +/- 8 mumol/h) occurring at 0-6 h after the load and rapidly declining thereafter, indicated the lower excretion of TP compared with its metabolites. N3-demethylation of TP accounted for 34 +/- 6% of the urinary metabolites, N1-demethylation of TP for 15 +/- 3% and C8-oxidation of TP for 51 +/- 9%. C8-oxidation of 1-X and 3-X was 93 +/- 4%, and 9 +/- 4%, respectively, of the excreted amount of monomethylxanthine plus formed monomethylurate. Since the extent of all metabolic reactions remained constant during the load, it is suggested that TP is metabolized by hepatic reactions that occurred simultaneously and not sequentially.