Relationship of urinary metabolites of theophylline to serum theophylline levels

Abstract

Using high‐pressure liquid chromatography, we have quantitated the theophylline metabolites in the 24‐hr urines of 15 patients in a clinical ward who had been receiving 800 or 1,200 mg of aminophylline /24 hr in divided oral doses. Mean values for the theophylline‐derived urine products were as follows: unchanged theophylline, 7.7 ± 6.1%; 3‐methylxanthine, 36.2 ± 7.3%; 1,3‐dimethyluric acid, 39.6 ± 4.5%; and 1‐methyluric acid, 16.5 ± 3.3%. These data are consistent with those earlier reported for theophylline metabolism in man with other methodology. The fractional contents of urine products were variably related to trough serum theophylline levels, the latter determined by the Schack and Waxler method. There was a significant direct correlation between serum theophylline levels and the urine theophylline fraction, and a significant inverse correlation between serum theophylline and the urine 3‐methylxanthine fraction. Urinary 3‐methylxanthine and 1,3‐dimethyluric acid were inversely related, implicating competition for substrate. The urine content of 1,3‐dimethyluric acid and 1‐methyluric acid diverged as serum theophylline increased, suggesting that the former may give rise to the latter by a rate‐limiting demethylation reaction. The data suggest that the 1‐demethylation of theophylline to 3‐methylxanthine is the dominant reaction determining serum theophylline.