Utilization of Human iPS Cells for Evaluation of Drug Disposition and Mucosal Damages in the Small Intestine].

Takahiro Iwao

Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 2023

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The expression of multiple drug transporters and drug-metabolizing enzymes in the small intestine entails a detailed evaluation of the intestinal drug absorption in light of the contribution of these pharmacokinetic-related molecules. The intestinal mucosal damage and barrier disruption caused by diseases and xenobiotics influences health. Therefore, developing models to evaluate drug disposition and mucosal damage in humans is essential. We generated intestinal models from human induced pluripotent stem (iPS) cells and evaluated the availability of the models. The human iPS cell-derived intestinal epithelial cells demonstrated enhanced cellular uptake and multiple efflux transporters. The CYP3A4/5 activity of the human iPS cell-derived intestinal epithelial cells was comparable to that of the human primary enterocytes. Moreover, the correlation between the fraction absorbed (Fa) and apparent permeability coefficient (Papp) of drugs in human iPS cell-derived intestinal epithelial cells was better than in Caco-2 cells, except for the CYP3A4 substrates. Furthermore, we established a method for the differentiation of intestinal organoids from human iPS cells. The budding-like intestinal organoids consisted of various intestinal cells. The organoids demonstrated intestinal mucosal damage caused by tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β), the main factors of inflammatory bowel diseases. Furthermore, when the organoids were dissociated and seeded on cell culture inserts, transepithelial electrical resistant values-an index of barrier function-increased gradually. These results demonstrate that human iPS cell-derived intestinal epithelial cells and intestinal organoids could be applied to evaluate intestinal drug disposition and mucosal damage.

Citation

Takahiro Iwao. Utilization of Human iPS Cells for Evaluation of Drug Disposition and Mucosal Damages in the Small Intestine]. Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan. 2023;143(3):243-247