Developmental changes in urinary elimination of theophylline and its metabolites in pediatric patients.
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.
Tateishi
T
T
Department of Pharmacology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
Asoh
M
M
Yamaguchi
A
A
Yoda
T
T
Okano
Y J
YJ
Koitabashi
Y
Y
Kobayashi
S
S
D000375:Aging / Q000652:urine*; D001049:Apnea / Q000378:metabolism*; D001249:Asthma / Q000378:metabolism*; D002675:Child, Preschool; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D013806:Theophylline / Q000652:urine*; D014527:Uric Acid / Q000031:analogs & derivatives / Q000652:urine; D014970:Xanthines / Q000652:urine
D014970:Xanthines; D014527:Uric Acid; C030530:1-methyluric acid; D013806:Theophylline; C031274:1,3-dimethyluric acid; D019388:Cytochrome P-450 CYP1A2; C029703:3-methylxanthine