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Published on: March 8, 2024
Age-Specific ADME Gene Expression in Infant Intestinal Enteroids
Eva J Streekstra1,2, Tom Scheer-Weijers1, Michael Bscheider3
1Department of Pharmacy, Division of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
Insights
Pediatric enteroids cultured from infant tissue maintain drug transporter and enzyme gene expression patterns. This supports their use in predicting pediatric drug safety and optimizing dosing regimens.
Area of Science:
- Pharmacology and Toxicology
- Developmental Biology
- Gastroenterology
Background:
- Childhood drug disposition is significantly influenced by developmental changes and environmental factors.
- Optimizing pediatric drug dosing requires understanding age-dependent drug absorption, distribution, metabolism, and excretion (ADME) biology.
- Existing models often lack the age-specific representation needed for accurate pediatric drug development.
Purpose of the Study:
- To establish and characterize age-specific enteroid cultures from infant intestinal tissue.
- To investigate the expression of key drug transporters and metabolizing enzymes in these enteroids.
- To assess the potential of pediatric enteroids as a model for predicting drug behavior in children.
Main Methods:
- Cultured 3D self-organizing enteroids from fresh infant (n=8) and adult (n=3) intestinal tissues.
- Determined gene expression of drug transporters (P-gp, BCRP, MRP2, PEPT1) and metabolizing enzymes (CYP3A4, CYP2C18, UGT1A1) via RT-qPCR.
- Compared gene expression in enteroids versus original tissue and assessed stability across enteroid passages.
Main Results:
- Enteroids successfully recapitulated gene expression patterns of key ADME genes found in native tissues.
- Expression levels of P-gp, BCRP, MRP2, and CYP3A4 were similar between tissues and enteroids.
- Similar maturational patterns were observed for several key genes, indicating preserved biological relevance.
Conclusions:
- Pediatric enteroids maintain the maturational patterns of clinically relevant ADME genes, mirroring native tissue.
- These findings represent a significant step towards utilizing pediatric enteroids in drug development for improved safety predictions.
- Pediatric enteroids offer a promising platform for age-specific studies of drug exposure and intestinal safety in pediatric populations.
Abstract:
In childhood, developmental changes and environmental interactions highly affect orally dosed drug disposition across the age range. To optimize dosing regimens and ensure safe use of drugs in pediatric patients, understanding this age-dependent biology is necessary. In this proof-of-concept study, we aimed to culture age-specific enteroids from infant tissue which represent its original donor material, specifically for drug transport and metabolism. Enteroid lines from fresh infant tissues (n = 8, age range: 0.3-45 postnatal weeks) and adult tissues (n = 3) were established and expanded to 3D self-organizing enteroids. The gene expression of drug transporters P-gp (ABCB1), BCRP (ABCG2), MRP2 (ABCC2), and PEPT1 (SLC15A1) and drug metabolizing enzymes CYP3A4, CYP2C18, and UGT1A1 was determined with RT-qPCR in fresh tissue and its derivative differentiated enteroids. Expression levels of P-gp, BCRP, MRP2, and CYP3A4 were similar between tissues and enteroids. PEPT1 and CYP2C18 expression was lower in enteroids compared to that in the tissue. The expression of UGT1A1 in the tissue was lower than that in enteroids. The gene expression did not change with the enteroid passage number for all genes studied. Similar maturational patterns in tissues and enteroids were visually observed for P-gp, PEPT1, MRP2, CYP3A4, CYP2C18, and VIL1. In this explorative study, interpatient variability was high, likely due to the diverse patient characteristics of the sampled population (e.g., disease, age, and treatment). To summarize, maturational patterns of clinically relevant ADME genes in tissue were maintained in enteroids. These findings are an important step toward the potential use of pediatric enteroids in pediatric drug development, which in the future may lead to improved pediatric safety predictions during drug development. We reason that such an approach can contribute to a potential age-specific platform to study and predict drug exposure and intestinal safety in pediatrics.
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