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 a nd its five metabolites were separated and quantified by combining hig h-performance liquid chromatography and capillary electrophoresis. In addition to TP, 1,3-U, 3-X and 1-U were consistently found in plasma a nd saliva. The area under the plasma concentration-time curve (AUG) sh owed that TP accounted for 91 +/- 4% (mean +/- SD) of the total AUC in plasma with 1,3-U accounting for 3.1 +/- 1.3%, 3-X for 3.4 +/- 1.8% a nd 1-U for 2.5 +/- 1.5%. The urine analyses showed that unchanged TP a ccounted for 19 +/- 5% of total excretion, the remainder being 1, 3-di methyluric acid (1,3-U, 41 +/- 6%), 1-methylxanthine (1-X, 2 +/- 0.8%) , 1-methyluric acid (1-U, 26 +/- 6%), 3-methyxanthine (3-X, 11 +/- 3%) and 3-methyluric acid (3-U, 1 +/- 0.3%). Highest excretion rates were observed for 1,3-U (70 +/- 29 mu mol/h), 1-U (40 +/- 26 mu mol/h) and 3-X (20 +/- 15 mu mol/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 mu mol/h) occurring at 0-6 h after the load and rapidly declining thereafter, indicated the lower excretion of TP comp ared with its metabolites. N3-demethylation of TP accounted for 34 +/- 6% of the urinary metabolites, N1-demethylation of TP for 15 +/- 3% a nd C8-oxidation of TP for 51 +/- 9%. C8-oxidation of l-X and 3-X was 9 3 +/- 4% and 9 +/- 4%, respectively, of the excreted amount of monomet hylxanthine plus formed monomethylurate. Since the extent of all metab olic reactions remained constant during the load, it is suggested that TP is metabolized by hepatic reactions that occurred simultaneously a nd not sequentially.