TY - JOUR T1 - Pediatric Development of Glucuronidation: The Ontogeny of Hepatic UGT1A4 JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1587 LP - 1592 DO - 10.1124/dmd.107.015214 VL - 35 IS - 9 AU - Shogo J. Miyagi AU - Abby C. Collier Y1 - 2007/09/01 UR - http://dmd.aspetjournals.org/content/35/9/1587.abstract N2 - This article reports on the development of UDP-glucuronosyltransferase (UGT) enzyme activity in pediatric livers. The substrates 4-methylumbelliferone (4MU) and trifluoperazine (TFP) were used as probes for general glucuronidation and specific UGT1A4 activity, respectively. The activity of hepatic β-glucuronidase enzymes was also determined so as to investigate the balance between glucuronide clearance and systemic recirculation. UGT activity toward 4MU reached maximum levels by 20 months of age, whereas the activity of β-glucuronidase was highest in the neonatal liver and decreased to steady-state adult levels by 4 months. The average Vmax and Km values for UGT1A4 in pediatric samples were 151.9 ± 63.5 pmol/min/mg protein and 14.4 ± 9.6 μM, respectively. Average Vmax was understandably low because of developmental dynamics, but Km was similar to values reported elsewhere. When a constant rate of enzyme development is assumed, maximum activity of UGT1A4 occurs at 1.4 years of age. When the intrinsic hepatic clearance of TFP was scaled with an allometric model, hepatic clearance of TFP by UGT1A4 did not reach maximum levels until 18.9 years of age and scaled results underestimated reported in vivo clearances in adult males. No significant differences in UGT activities or hepatic clearance were observed with gender or ethnicity. The developmental dynamics of most drug-metabolizing enzymes are unknown, and this article contains, to our knowledge, the first description of the development of a single UGT isoform in childhood. Ultimately, work such as this is important for predicting drug responses and for developing and evaluating new medications in children. The American Society for Pharmacology and Experimental Therapeutics ER -