Developmental aspects of theophylline metabolism in premature infants

The metabolic degradation of theophylline was studied in nine premature infants with postconception ages of 28 to 42 wk. Urinary and plasma metabolites (caffeine; theobromine; 3-methylxanthine; 1,3-dimethyluric acid; and 1-methyluric acid) and unchanged theophylline were analyzed with selected ion monitoring gas chromatography-mass spectrometry. The anticipated decrease in plasma caffeine (which is absent in adult human and children) did not occur in the postconception age range studied, but the urinary percentages of unchanged theophylline decreased from 61% at a postconception age of 28 to 32 wk to 43% at 38 to 42 wk. This suggests increasing theophylline metabolism with age due to developing hepatic cytochrome P-450 enzyme systems. The increased degradation of theophylline is largely explained by the production of 1,3-dimethyluric acid (from 20% to 34%). In infants of an older postconception age, theobromine, a caffeine metabolite, was also detected. To explain the difference of caffeine pathway between adults and premature infants, it is hypothesized that the caffeine pathway of theophylline is equally active in both age groups. The absence of caffeine metabolite in adults is due to the maturing caffeine-metabolizing enzymes, which degrade caffeine immediately to its metabolites.