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Tissues of the small intestine are crucial to understanding drug disposition because these tissues regulate the bioavailability of drugs. However, no evaluation system is currently available for precise and comprehensive analysis of intestinal pharmacokinetics. To address this, functional intestinal epithelial cells were generated from human induced pluripotent stem (iPS) cells for use in pharmacokinetic studies. An improved intestinal differentiation method was established by screening a variety of small molecule compounds against cells during differentiation. The mRNA expression levels of intestinal markers, drug transporters, and CYP3A4 were found to increase following treatment with compounds that act as inhibitors of mitogen-activated protein kinase, DNA methyltransferase, and transforming growth factor-β. Therefore, we inferred that these compounds enhanced differentiation into intestinal epithelial cells. The differentiated intestinal epithelial cells in the presence of these compounds possessed drug-metabolizing enzyme activities, such as those of CYPs, UDP-glucuronosyltransferase, and sulfotransferase. In addition, these cells had the ability to induce CYP3A4 in the presence of 1α,25-dihydroxyvitamin D 3 . The differentiated intestinal epithelial cells seeded on cell culture inserts formed loose-tight junctions, similar to those in the human small intestine, rather than Caco-2 cells. The cells exhibited polarity, such as apical and basal sides. We also demonstrated that the uptake and efflux transport activities in the cells occurred via peptide transporter and breast cancer resistance protein, respectively. Taken together, it was suggested that human iPS cell-derived intestinal epithelial cells are pharmacokinetically functional, and represent a promising model system for pharmacokinetic studies of drug candidates.

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Development of an &lt;i&gt;In Vitro&lt;/i&gt; System for Evaluating Intestinal Drug Disposition Using Human Induced Pluripotent Stem Cell-Derived Intestinal Epithelial Cells