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Postnatal Hepatobiliary and Gastrointestinal Systems Development and Impact on ADME

Wendy G Halpern1, April Kluever2, Armando R Irizarry Rovira3

  • 17412Genentech, South San Francisco, CA, USA.

Toxicologic Pathology
|October 5, 2021
PubMed

Insights

Postnatal development impacts organ sensitivity to toxicity, affecting drug disposition and safety assessments. Understanding these developmental changes in systems like the gastrointestinal tract and liver is crucial for accurate risk evaluation.

Area of Science:

  • Developmental toxicology
  • Pharmacokinetics and drug metabolism
  • Neonatal and juvenile physiology

Background:

  • Postnatal development influences target organ sensitivity and toxicological exposure.
  • Neonatal gastrointestinal tract (GIT) maturation is critical for nutrient absorption and drug disposition.
  • Hepatic maturation in juvenile rodents involves changes in drug-metabolizing enzymes and transporters.

Purpose of the Study:

  • To highlight the impact of postnatal development on toxicity.
  • To emphasize the importance of understanding developmental changes in drug disposition.
  • To inform the interpretation of developmental toxicity studies.

Main Methods:

  • Review of physiological changes in neonatal and juvenile GIT and liver.
  • Analysis of how these changes affect drug pharmacokinetics and toxicity.
  • Discussion of the role of animal models in developmental toxicity assessment.

Main Results:

  • Gastrointestinal tract and hepatic functions mature postnatally, influencing drug disposition.
  • Maturation involves changes in motility, enzyme/transporter function, permeability, and microbiome.
  • These developmental changes can affect rodent pharmacokinetics and toxicity profiles.

Conclusions:

  • Interpreting developmental toxicity requires knowledge of developing human and nonclinical systems.
  • Pilot studies in juvenile rodents can help mitigate toxicity related to drug disposition.
  • Accurate pediatric dose estimation necessitates understanding developmental pharmacokinetics.

Keywords:
developmental pathologydrug developmentgastrointestinal systemhepatobiliary systemjuvenile toxicitynutrition/food productspreclinical safety assessment/risk management

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