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Enteroids to Study Pediatric Intestinal Drug Transport
Eva J Streekstra1,2, Marit Keuper-Navis2,3, Jeroen J M W van den Heuvel1
1Division of Pharmacology and Toxicology, Department of Pharmacy, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
Molecular Pharmaceutics
|September 16, 2024
Summary
Pediatric enteroids accurately model intestinal drug transport and gene expression, showing age-related pharmacokinetic differences similar to human tissues. This validates enteroids as a promising in vitro tool for pediatric drug development.
Area of Science:
- Pharmacokinetics and Drug Metabolism
- Gastroenterology and Hepatology
- Pediatric Pharmacology
Background:
- Intestinal maturation post-birth significantly alters drug pharmacokinetics (PK), impacting pediatric drug safety and efficacy.
- Limited understanding exists regarding ontogeny-related PK patterns in the developing pediatric intestine.
- Human enteroid monolayers offer a potential in vitro model for studying pediatric intestinal drug transport.
Purpose of the Study:
- To evaluate the accuracy of human enteroid monolayers for studying drug transport in the pediatric intestine.
- To compare drug transporter functionality and gene expression in pediatric and adult enteroid monolayers versus intestinal tissue.
- To investigate age-related variations in drug transport and metabolism using enteroid models.
Main Methods:
- Cultured enteroid monolayers from pediatric and adult donors.
- Performed bidirectional drug transport experiments using enalaprilat, propranolol, talinolol, and rosuvastatin.
- Analyzed drug transporter expression (P-gp, BCRP) and ADME-related gene patterns via RNA sequencing in enteroids and tissue explants (Ussing chamber).
Main Results:
- Efflux transport by P-gp and BCRP was comparable between enteroids and tissue.
- RNA sequencing revealed age-related variations in drug metabolism between neonates and adults in both enteroids and tissue.
- Drug transport in enteroids generally aligned with ex vivo tissue experiments, supporting enteroids as a valid model.
Conclusions:
- Pediatric enteroid monolayers demonstrate comparable drug transporter functionality and gene expression patterns to intestinal tissue.
- Enteroids effectively model age-related pharmacokinetic differences observed in vivo, particularly between neonates and adults.
- Human pediatric enteroids represent a valuable and versatile in vitro platform for investigating pediatric drug transport and developmental changes.
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