Age-Specific ADME Gene Expression in Infant Intestinal Enteroids.

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.