Received for publication February 20, 2007.
Revised June 4, 2007.
Accepted for publication June 7, 2007.

Pediatric development of glucuronidation: the ontogeny of hepatic UGT1A4

Abstract

This paper reports on the development of Uridine diphosphate 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 -glucuronidase enzymes was also determined so as to investigate the balance between glucuronide clearance and systemic re-circulation. UGT activity towards 4MU reached maximum levels by 20 months of age, while the activity of -glucuronidase was highest in the neonatal liver and decreased to steady-state adult levels by 4 months. The average Vmax and Km 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 due to developmental dynamics, but Km was similar to those 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 clearances were observed with gender or ethnicity. The developmental dynamics of most drug metabolizing enzymes are unknown and this paper contains 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.

Key words: developmental pharmacology, pharmacokinetic modeling, phase II drug metabolism, physiologically-based pharmacokinetics, UDP glucuronyltransferases