Metabolism of theophylline (1,3-dimethylxanthine) in man.

The intermediary metabolism of theophylline has been the subject of a number of studies, but its fate in the body is still unsettled. Kruger and Schmidt (1) working with dogs reported that the administration of theophylline to dogs is followed by the appearance of 3-methylxanthine in the urine. Myers and Wardell (2) and Buchanan, Christman, and Block (3) showed that ingestion of theophylline in man is followed by an increased urinary excretion of phosphotungstic acid-reducing material. The former investigators were unable to determine whether the increase in reducing material was due to uric acid or to a methyluric acid. The latter were able to show, by the use of uricase, that the increment in reducing material is not uric acid. They concluded that a large part of the theophylline is excreted as 1-methyluric but suggested that 3-methyluric or 1,3-dimethyluric acid may also be formed. None of these compounds was actually isolated in support of their hypothesis. Myers and Hanzal (4) working with the Dalmatian dog concluded, from the coloryielding value of the phosphotungstic acid-reducing material, that theophylline is excreted mainly in the form of 1,3-dimethyluric acid. In a preliminary report, Weinfeld (5) suggested that l-methyland 1,3-dimethyluric acid are excreted in rabbit urine after feeding theophylline. The compounds were identified by their behavior on paper chromatograms. The utilization of counter-current extraction and ion exchange chromatography have made it possible to obtain definitive information concerning a part of the metabolic pathway of theophylline. The present paper reports studies on the fate of theophylline in man and describes the isolation and characterization of 1,3:dimethyluric acid, a major transformation product.