Usefulness of Human Jejunal Spheroid-Derived Differentiated Intestinal Epithelial Cells for the Prediction of Intestinal Drug Absorption in HumansS

This study aimed to demonstrate the usefulness of human jejunal spheroid-derived differentiated intestinal epithelial cells as a novel in vitro model for clarifying the impact of intestinal drug-metabolizing enzymes and transporters on the intestinal absorption of substrate drugs in humans. Three-dimensional human intestinal spheroids were successfully established from surgical human jejunal specimens and expanded for a long period using L-WRN-conditioned medium, which contains Wnt3a, R-spondin 3, and noggin. The mRNA expression levels of intestinal pharmacokinetics-related genes in the human jejunal spheroid-derived differentiated intestinal epithelial cells were drastically increased over a 5-day period after seeding compared with those in human jejunal spheroids and were approximately the same as those in human jejunal tissue over a culture period of at least 13 days. Activities of typical drug-metabolizing glucuronosyltransferase 1A, and carboxylesterase 2] and uptake/ efflux transporters [peptide transporter 1/solute carrier 15A1], P-glycoprotein, and breast cancer resistance protein) in the differentiated cells were confirmed. Furthermore, intestinal availability (Fg) values estimated from the apical-to-basolateral permeation clearance across cell monolayer showed a good correlation with the in vivo Fg values in humans for five CYP3A substrate drugs (Fg range, 0.35-0.98). In conclusion, the functions of major intestinal drug-metabolizing enzymes and transporters could be maintained in human jejunal spheroid-derived differentiated intestinal epithelial cells. This model would be useful for the quantitative evaluation of the impact of intesti-nal drug-metabolizing enzymes and transporters on the intestinal absorption of substrate drugs in humans.

Automated summary

This study has demonstrated the usefulness of human jejunal spheroid-derived differentiated intestinal epithelial cells as an in vitro model for studying the impact of intestinal drug-metabolizing enzymes and transporters on substrate drugs' absorption in humans. The model was able to maintain the functions of major intestinal drug-metabolizing enzymes and transporters. It could be used for quantitative evaluation of the impact of these enzymes and transporters on drug absorption.