Pharmacokinetic functions of human induced pluripotent stem cell-derived small intestinal epithelial cells

• Published in: Drug metabolism and pharmacokinetics Vol. 35; no. 4; pp. 374 - 382
• Main Authors: Kabeya, Tomoki, Mima, Shinji, Imakura, Yuki, Miyashita, Toshihide, Ogura, Izumi, Yamada, Tadanori, Yasujima, Tomoya, Yuasa, Hiroaki, Iwao, Takahiro, Matsunaga, Tamihide
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2020
• Subjects: Alkanesulfonic Acids - pharmacokinetics; Caco-2 Cells; Caco-2 cells; Cells, Cultured; Cyclosporins - pharmacokinetics; CYP3A4/5 activities; Differentiation; Digoxin - pharmacokinetics; Dipeptides - pharmacokinetics; Drug membrane permeability; Epithelial Cells - metabolism; Forskolin; Human iPS cell-derived small intestinal epithelial cells; Human primary small intestinal cells; Humans; Ibuprofen - pharmacokinetics; Induced Pluripotent Stem Cells - metabolism; Intestine, Small - cytology; Intestine, Small - metabolism; Morpholines - pharmacokinetics; Drug membrane permeability; CYP3A4/5 activities; Forskolin; Human iPS cell-derived small intestinal epithelial cells; Human primary small intestinal cells; Differentiation; Caco-2 cells
• ISSN: 1347-4367; 1880-0920; 1880-0920
• DOI: 10.1016/j.dmpk.2020.04.334

To develop a novel intestinal drug absorption system using intestinal epithelial cells derived from human induced pluripotent stem (iPS) cells, the cells must possess sufficient pharmacokinetic functions. However, the CYP3A4/5 activities of human iPS cell-derived small intestinal epithelial cells prepared using conventional differentiation methods is low. Further, studies of the CYP3A4/5 activities of human iPS-derived and primary small intestinal cells are not available. To fill this gap in our knowledge, here we used forskolin to develop a new differentiation protocol that activates adenosine monophosphate signaling. mRNA expressions of human iPS cell-derived small intestinal epithelial cells, such as small intestine markers, drug-metabolizing enzymes, and drug transporters, were comparable to or greater than those of the adult small intestine. The activities of CYP3A4/5 in the differentiated cells were equal to those of human primary small intestinal cells. The differentiated cells had P-glycoprotein and PEPT1 activities equivalent to those of Caco-2 cells. Differentiated cells were superior to Caco-2 cells for predicting the membrane permeability of drugs that were absorbed through a paracellular pathway and via drug transporters. In summary, here we produced human iPS cell-derived small intestinal epithelial cells with CYP3A4/5 activities equivalent to those of human primary small intestinal cells. [Display omitted]