Developmental changes in urinary elimination of theophylline and its metabolites in pediatric patients

We investigated the developmental changes in the pattern of urinary metabol ites of theophylline, a substrate for CYP1A2, to study when CYP1A2, which i s absent in the perinatal period, fully develops during childhood. The urin ary ratios of three metabolites (1-methyluric acid, 3-methylxanthine, and 1 ,3-dimethyluric acid) to theophylline in patients over 3 y of age show a mu ch larger interindividual variation compared with those under 3 y of age, a nd the mean Values of the ratios in patients over 3 y of age were greater t han those in patients under 1 y of age. The urinary ratio of 1,3-dimethylur ic acid (a metabolite generated by several cytochrome P450s) to 3-methylxan thine or 1-methyluric acid (metabolites generated by CYP1A2 exclusively) se emed to be relatively constant over 3 y of age; in patients under 3 y of ag e, these ratios were much higher than those in patients over 3 y of age. Th e urinary ratio of 1-methyluric acid to 3-methylxanthine or 3-methylxanthin e to 1-methyluric acid seemed to be relatively invariable in all patients e xcept those less than I y of age. These findings suggest that CYP1A2 activi ty may be programmed to mature by around 3 y of age and that CYP1A2 probabl y plays a major role in theophylline 8-hydroxylation at a therapeutic conce ntration after the full development of CYP1A2 activity.