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Developmental changes in urinary elimination of theophylline and its metabolites in pediatric patients
T Tateishi1, M Asoh, A Yamaguchi
1Department of Pharmacology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
Insights
Cytochrome P450 1A2 (CYP1A2) activity matures by age 3, influencing theophylline metabolism. Urinary metabolite ratios reveal developmental changes in CYP1A2 function during childhood.
Area of Science:
- Pharmacokinetics
- Drug metabolism
- Pediatric pharmacology
Background:
- Theophylline is metabolized by Cytochrome P450 1A2 (CYP1A2).
- CYP1A2 is absent at birth and develops postnatally.
- Understanding CYP1A2 developmental trajectory is crucial for pediatric drug dosing.
Purpose of the Study:
- To investigate the developmental maturation of CYP1A2 activity in children.
- To determine the age at which CYP1A2 function is fully established.
- To analyze the impact of CYP1A2 development on theophylline metabolism.
Main Methods:
- Analysis of urinary theophylline metabolites in pediatric patients.
- Calculation of metabolite-to-theophylline ratios.
- Comparison of metabolite ratios across different age groups.
Main Results:
- Urinary metabolite ratios showed increased interindividual variation after 3 years of age.
- Mean metabolite ratios were higher in children over 3 years compared to infants under 1 year.
- Ratios of CYP1A2-specific metabolites to other metabolites indicated maturation by 3 years of age.
Conclusions:
- CYP1A2 activity appears to mature by approximately 3 years of age.
- CYP1A2 plays a significant role in theophylline 8-hydroxylation at therapeutic concentrations post-maturation.
- These findings have implications for optimizing theophylline therapy in children.
Abstract:
We investigated the developmental changes in the pattern of urinary metabolites of theophylline, a substrate for CYP1A2, to study when CYP1A2, which is absent in the perinatal period, fully develops during childhood. The urinary 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 much larger interindividual variation compared with those under 3 y of age, and the mean values of the ratios in patients over 3 y of age were greater than those in patients under 1 y of age. The urinary ratio of 1,3-dimethyluric acid (a metabolite generated by several cytochrome P450s) to 3-methylxanthine or 1-methyluric acid (metabolites generated by CYP1A2 exclusively) seemed to be relatively constant over 3 y of age; in patients under 3 y of age, these ratios were much higher than those in patients over 3 y of age. The urinary ratio of 1-methyluric acid to 3-methylxanthine or 3-methylxanthine to 1-methyluric acid seemed to be relatively invariable in all patients except those less than 1 y of age. These findings suggest that CYP1A2 activity may be programmed to mature by around 3 y of age and that CYP1A2 probably plays a major role in theophylline 8-hydroxylation at a therapeutic concentration after the full development of CYP1A2 activity.