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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 2/2019

01-02-2019 | Review Article

The Ontogeny of UDP-glucuronosyltransferase Enzymes, Recommendations for Future Profiling Studies and Application Through Physiologically Based Pharmacokinetic Modelling

Authors: Justine Badée, Stephen Fowler, Saskia N. de Wildt, Abby C. Collier, Stephan Schmidt, Neil Parrott

Published in: Clinical Pharmacokinetics | Issue 2/2019

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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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Metadata
Title
The Ontogeny of UDP-glucuronosyltransferase Enzymes, Recommendations for Future Profiling Studies and Application Through Physiologically Based Pharmacokinetic Modelling
Authors
Justine Badée
Stephen Fowler
Saskia N. de Wildt
Abby C. Collier
Stephan Schmidt
Neil Parrott
Publication date
01-02-2019
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 2/2019
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-018-0681-2

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