N. Rodopoulos et A. Norman, ELIMINATION OF THEOPHYLLINE METABOLITES IN HEALTHY-ADULTS, Scandinavian journal of clinical & laboratory investigation, 57(3), 1997, pp. 233-240
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.