Clinical Pharmacokinetics

, Volume 58, Issue 2, pp 189–211 | Cite as

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

  • Justine Badée
  • Stephen Fowler
  • Saskia N. de Wildt
  • Abby C. Collier
  • Stephan Schmidt
  • Neil ParrottEmail author
Review Article


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.



Bovine serum albumin


Intrinsic clearance


Cytochrome P450


Drug-metabolizing enzymes


Human liver microsomes


In vitro–in vivo extrapolation


Michaelis–Menten constant


Physiologically-based pharmacokinetic


Uridine diphosphate-glucuronic acid




Maximum velocity


Compliance with Ethical Standards


This work was supported by the Roche Postdoc Fellowship Program.

Conflict of interest

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.

Supplementary material

40262_2018_681_MOESM1_ESM.docx (319 kb)
Supplementary material 1 (DOCX 319 kb)


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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Justine Badée
    • 1
  • Stephen Fowler
    • 2
  • Saskia N. de Wildt
    • 3
    • 4
  • Abby C. Collier
    • 5
  • Stephan Schmidt
    • 1
  • Neil Parrott
    • 2
    Email author
  1. 1.Department of Pharmaceutics, Center for Pharmacometrics and Systems PharmacologyUniversity of Florida at Lake NonaOrlandoUSA
  2. 2.Pharmaceutical Sciences, Roche Pharma Research and Early DevelopmentRoche Innovation Centre BaselBaselSwitzerland
  3. 3.Department of Pharmacology and ToxicologyRadboud UniversityNijmegenThe Netherlands
  4. 4.Intensive Care and Department of Paediatric SurgeryErasmus MC Sophia Children’s HospitalRotterdamThe Netherlands
  5. 5.Faculty of Pharmaceutical SciencesThe University of British ColumbiaVancouverCanada

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