Pediatric Development of Glucuronidation: The Ontogeny of Hepatic UGT1A4

Abstract

ABSTRACT: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 ␤-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 ␤-glucuronidase was highest in the neonatal liver and decreased to steady-state adult levels by 4 months. The average V max and K m values for UGT1A4 in pediatric samples were 151.9 ؎ 63.5 pmol/min/mg protein and 14.4 ؎ 9.6 M, respectively. Average V max was understandably low because of developmental dynamics, but K m 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 Development of UDP-Glucuronosyltransferases 1A1 and 1A6 in the Pediatric Liver

“…The results for UGT1A1 are similar to, and supported by, published studies into UGT1A4 (Miyagi and Collier, 2007) and 2B7 (Zaya et al, 2006). In this study, the in silico models indicate that UGT1A1 enzyme activity is present, but it is very low at birth and increases to a plateau after 3.8 months.…”

“…For individual UGT isoforms, postnatal development has been described for UGT1A4 (Miyagi and Collier, 2007) and UGT2B7 (Zaya et al, 2006). Herein, we extend knowledge in this area by investigating the ontogeny of UGT1A1 and 1A6.…”

Neonatal Development of Hepatic UGT1A9: Implications of Pediatric Pharmacokinetics

“…The development of UGT1A9 is age-dependent, reflecting published studies for UGT1A4 (Miyagi and Collier, 2007), UGT1A1/1A6 FIG. 1.…”

Change in Pharmacokinetics of Mycophenolic Acid as a Function of Age in Rats and Effect of Coadministered Amoxicillin/Clavulanate

“…13) In human liver, β-glucuronidase activity to hydrolyze MPAG into MPA is the highest in newborns and falls to the adult level by the age of 4 months. 14) In rat liver, β-glucuronidase activity shows a sharp increase 2-3 d after birth, peaks at 20-30 d and remains at a plateau during 50-90 d. 15) If the difference in disposition kinetics between 4-and 12-week-old rats were caused by β-glucuronidase activity in liver, the plasma concentration of 4-week-old rats should be higher than that of 12-week-old rats, whereas the opposite was the case. On the other hand, the level of β-glucuronidase activity in rat intestine appeared to be almost constant.…”