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

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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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Abbreviations

BSA:

Bovine serum albumin

CLint:

Intrinsic clearance

CYP:

Cytochrome P450

DME:

Drug-metabolizing enzymes

HLM:

Human liver microsomes

IVIVE:

In vitro–in vivo extrapolation

Km:

Michaelis–Menten constant

PBPK:

Physiologically-based pharmacokinetic

UDPGA:

Uridine diphosphate-glucuronic acid

UGT:

UDP-glucuronosyltransferases

V max :

Maximum velocity

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Authors and Affiliations

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

    Justine Badée & Stephan Schmidt

  2. Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Centre Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland

    Stephen Fowler & Neil Parrott

  3. Department of Pharmacology and Toxicology, Radboud University, Nijmegen, The Netherlands

    Saskia N. de Wildt

  4. Intensive Care and Department of Paediatric Surgery, Erasmus MC Sophia Children’s Hospital, Rotterdam, The Netherlands

    Saskia N. de Wildt

  5. Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada

    Abby C. Collier

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  1. Justine Badée
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  2. Stephen Fowler
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  3. Saskia N. de Wildt
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  4. Abby C. Collier
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  5. Stephan Schmidt
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  6. Neil Parrott
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Correspondence to Neil Parrott.

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This work was supported by the Roche Postdoc Fellowship Program.

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Justine Badée, Stephen Fowler, Saskia N. de Wildt, Abby C. Collier, Stephan Schmidt and Neil Parrott have no conflicts of interest that are directly relevant to the content of this article.

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Badée, J., Fowler, S., de Wildt, S.N. et al. The Ontogeny of UDP-glucuronosyltransferase Enzymes, Recommendations for Future Profiling Studies and Application Through Physiologically Based Pharmacokinetic Modelling. Clin Pharmacokinet 58, 189–211 (2019). https://doi.org/10.1007/s40262-018-0681-2

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