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The Ontogeny of UDP-glucuronosyltransferase Enzymes, Recommendations for Future Profiling Studies and Application

Justine Badée¹, Stephen Fowler², Saskia N de Wildt^3,4

¹Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, University of Florida at Lake Nona, Orlando, FL, USA.

Clinical Pharmacokinetics

|June 5, 2018

Insights

Understanding age-related changes in UDP-glucuronosyltransferases (UGTs) is crucial for safe pediatric drug development. This review highlights UGT variability and offers best practices for improving pediatric pharmacokinetics data.

Area of Science:

Pharmacology and Toxicology
Drug Metabolism and Pharmacokinetics
Pediatric Drug Development

Background:

Limited understanding of pediatric drug pharmacokinetics, especially in neonates and infants, poses challenges in drug development.
Physiologically based pharmacokinetic (PBPK) models incorporating cytochrome P450 ontogeny have advanced understanding of drug exposure in children.
UDP-glucuronosyltransferase (UGT)-mediated metabolism, a key xenobiotic conjugation pathway, remains poorly understood regarding age-related changes.

Purpose of the Study:

To conduct a comprehensive literature review on age-related changes in UDP-glucuronosyltransferases (UGTs).
To summarize current knowledge on UGT expression and activity across different age groups.
To identify and discuss clinical and experimental sources of variance in UGT-mediated metabolism.

Main Methods:

Systematic literature survey of studies investigating UDP-glucuronosyltransferases (UGTs).
Analysis of age-dependent changes in UGT isoforms' expression and activity.
Review of factors contributing to inter-individual and inter-laboratory variability in human liver microsomes.

Main Results:

Distinct differences in UDP-glucuronosyltransferase (UGT) isoform expression and activity are observed across various age groups.
Significant inter-individual and inter-laboratory variability exists in human liver microsome studies, partly due to non-standardized experimental conditions.
Current data on UGTs in pediatric populations show substantial variance, impacting quantitative clinical pharmacology.

Conclusions:

Age-specific differences in UDP-glucuronosyltransferase (UGT) activity necessitate tailored approaches for pediatric drug dosing.
Standardization of experimental conditions is essential to reduce variability in UGT research and improve data quality.
Implementing best practice recommendations can enhance the reliability of data for pediatric pharmacokinetics, leading to safer and more effective drug therapies.

Read full analysis

Abstract:

Limited understanding of drug pharmacokinetics in children is one of the major challenges in paediatric drug development. This is most critical in neonates and infants owing to rapid changes in physiological functions, especially in the activity of drug-metabolising enzymes. Paediatric physiologically based pharmacokinetic models that integrate ontogeny functions for cytochrome P450 enzymes have aided our understanding of drug exposure in children, including those under the age of 2 years. Paediatric physiologically based pharmacokinetic models have consequently been recognised by the European Medicines Agency and the US Food and Drug Administration as innovative tools in paediatric drug development and regulatory decision making. However, little is currently known about age-related changes in UDP-glucuronosyltransferase-mediated metabolism, which represents the most important conjugation reaction for xenobiotics. Therefore, the objective of the review was to conduct a thorough literature survey to summarise our current understanding of age-related changes in UDP-glucuronosyltransferases as well as associated clinical and experimental sources of variance. Our findings indicate that there are distinct differences in UDP-glucuronosyltransferase expression and activity between isoforms for different age groups. In addition, there is substantial variability between individuals and laboratories reported for human liver microsomes, which results in part from a lack of standardised experimental conditions. Therefore, we provide a number of best practice recommendations for experimental conditions, which ultimately may help improve the quality of data used for quantitative clinical pharmacology approaches, and thus for safe and effective pharmacotherapy in children.

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