Characterization of the Ontogeny of Hepatic UDP‐Glucuronosyltransferase Enzymes Based on Glucuronidation Activity Measured in Human Liver Microsomes

Abstract

An understanding of the postnatal development of hepatic UDP‐glucuronosyltransferase (UGT) enzymes is required for accurate prediction of the age‐dependent changes in pharmacokinetics of many drugs used in children. However, the maturation rate of hepatic UGT isoforms remains a major knowledge gap. This study aimed to establish the age‐associated changes in glucuronidation activity of 10 major hepatic UGT isoforms in humans, namely, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B4, UGT2B7, UGT2B10, UGT2B15, and UGT2B17. Human liver microsomes from pediatric and adult donors were incubated under optimized incubation conditions to assess the activity rates of hepatic UGT isoforms using a panel of 19 in vitro UGT probe substrates and clinically used drugs. Statistically strong correlations of glucuronidation activities allowed the ontogeny of UGT1A1, UGT1A4, UGT2B7, UGT2B10, and UGT2B15 to be established using multiple selective UGT substrates and matched human liver microsome samples. The postnatal development of hepatic UGTs is isoform‐dependent using either individual or cross‐correlated selective isoform substrates. Maximal adult activity was reached at different times ranging from within a month (UGT1A1, UGT2B4, UGT2B7, UGT2B10, and UGT2B15), during infancy (UGT1A3, UGT1A4, and UGT1A9), to adolescence (UGT1A6 and UGT2B17). This study provides an extensive characterization of the postnatal ontogeny profiles of hepatic UGT enzymes that are instrumental for predicting drug disposition via in vitro–in vivo extrapolation algorithms and verifying pharmacokinetic predictions against in vivo observations via pediatric physiologically based pharmacokinetic modeling in pediatric patients.

Pediatric Pharmacokinetics and Dose Predictions: A Report of a Satellite Meeting to the 10th Juvenile Toxicity Symposium

“…In agreement with previous literature, UGT1A4, UGT1A6, and UGT2B17 activities were found to increase from infant age to adulthood 3 . UGT2B17 increased slowly, with adult levels reached at adolescence.…”

Pharmacokinetics and Pharmacodynamics of Posaconazole

“…These children showed a higher inter-individual variability on CL/F compared to that of adults (63.0% vs. 24.2% or 37.9%) [40,41]. This might be partly attributable to the age-associated maturation of hepatic UGT1A4 [135].…”

Coexpression of Human Hepatic Uridine Diphosphate Glucuronosyltransferase Proteins: Implications for Ontogenetic Mechanisms and Isoform Coregulation

“…Studies focusing on individual isoforms have shown that the glucuronidation activities of human hepatic isoforms develop in an age‐dependent manner, and protein expression may not correlate with activity . The protein expression–enzyme activity disconnect demonstrated within the UGT enzymes during development, which has been comprehensively discussed, presents a challenge for accurately predicting drug biotransformation and, therefore, drug response in children. UGT proteins may be present in truncated or partially active forms.…”

“…This method could therefore complement proteomics approaches in which the protein is proteolytically degraded before quantitation of defined peptide fragments. We cannot, however, rule out the possibility that full‐length but inactive protein could be quantified using the blotting method; these inactive UGT proteins have generally been shown to exist in fetal and neonatal livers with activity being mature within approximately 24 months of life . In terms of practical applications for dose selection, these data imply that the allometric approach (down to 2 years of age) will give different data from a physiologically based pharmacokinetic approach and may be less accurate due to reliance on intrinsic clearances.…”