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Related Experiment Videos

Glucuronidation in humans. Pharmacogenetic and developmental aspects.

S N de Wildt1, G L Kearns, J S Leeder

  • 1Department of Pediatrics, Erasmus University and University Hospital, Rotterdam, The Netherlands. dewildt@alkg.azr.nl

Clinical Pharmacokinetics
|July 31, 1999
PubMed
Summary

Understanding drug metabolism in children is key. Uridine 5'-diphosphate (UDP)-glucuronosyltransferases (UGTs) are crucial, but their developmental and genetic aspects require more research for safer drug use in pediatrics.

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Area of Science:

  • Pharmacology and Toxicology
  • Developmental Biology
  • Genetics

Background:

  • Drug disposition significantly changes during human development, impacting drug clearance.
  • Metabolism, influenced by ontogeny and genetics, contributes to drug metabolism variability in children.
  • Conjugation pathways, particularly uridine 5"-diphosphate (UDP)-glucuronosyltransferases (UGTs), are vital for drug and endogenous substrate biotransformation.

Purpose of the Study:

  • To highlight the importance of understanding developmental and genetic factors in UGT activity for pediatric drug therapy.
  • To address the information gap concerning the ontogeny and pharmacogenetics of UGTs.
  • To emphasize the need for further research to improve clinical application of UGT knowledge.

Main Methods:

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  • Review of existing literature on UGT ontogeny and genetic polymorphisms.
  • Analysis of studies investigating UGT isoform specificity for various substrates.
  • Examination of clinical data related to UGT activity and adverse drug events in pediatric populations.

    • Main Results:

    • At least 10 UGT isoforms are identified, involved in metabolizing drugs (e.g., paracetamol) and endogenous compounds (e.g., bilirubin).
    • UGT2B7 is the only isoform with characterized ontogeny in vitro and in vivo; no general developmental pattern for other isoforms is established.
    • Genetic polymorphisms exist for UGTs, but their impact on drug metabolism is not fully understood due to overlapping specificities and lack of probe substrates.

    Conclusions:

    • Developmental and genetic factors significantly influence UGT activity, leading to inter- and intraindividual variability in drug disposition during childhood.
    • Current knowledge on UGT ontogeny and pharmacogenetics is insufficient for direct clinical application in pediatric drug therapy.
    • Further research on UGT pharmacogenetics and ontogeny is essential for translating scientific findings into effective clinical practice.