Theophylline metabolism in premature infants

The theophylline metabolite pattern in premature infants was studied with gas chromatography-mass spectrometry. The identities of metabolites were established by retention time indices and mass chromatograms. In the steady state of a multiple-dose regimen, the urinary metabolites of theophylline identified and quantified were caffeine (9.6 plus or minus 4.8%), theophylline (50.4 plus or minus 6.7%), 3-methylxanthine (1.3 plus or minus 0.7%), 1,3-dimethyluric acid (27.7% plus or minus 8.8%), and 1-methyluric acid (9.3 plus or minus 5.4%). Those in plasma were caffeine (21.4 plus or minus 6.1%), theophylline (73.6 plus or minus 6.5%), 3-methylxanthine (0.7 plus or minus 0.4%), 1,3-dimethyluric acid (2.6 plus or minus 1.2%), and 1-methyluric acid (0.6 plus or minus 0.3%). Occasionally, theobromine, the metabolic breakdown product of caffeine, was found in urine and plasma in small quantities. The demethylation pathway occurring predominantly in adults was substituted by N-methylation to caffeine in premature infants; the other major metabolic pathway of theophylline in adults, C-8 oxidation to 1,3-dimethyluric acid, was slightly diminished. We concluded that the enzyme systems responsible for the C-8 oxidation of theophylline are relatively active in premature infants and that the development of the enzyme systems responsible for oxidative demethylation of theophylline lags behind. The oxidation and demethylation pathways of theophylline in premature infants are significant.