Pharmacokinetic functions of human induced pluripotent stem cell-derived small intestinal epithelial cells
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 pr...
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| Published in | Drug metabolism and pharmacokinetics Vol. 35; no. 4; pp. 374 - 382 |
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| Main Authors | , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
England
Elsevier Ltd
01.08.2020
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| Abstract | 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.
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| AbstractList | 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.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. 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] 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. |
| Author | Kabeya, Tomoki Imakura, Yuki Yuasa, Hiroaki Mima, Shinji Yamada, Tadanori Miyashita, Toshihide Yasujima, Tomoya Iwao, Takahiro Matsunaga, Tamihide Ogura, Izumi |
| Author_xml | – sequence: 1 givenname: Tomoki surname: Kabeya fullname: Kabeya, Tomoki organization: Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan – sequence: 2 givenname: Shinji surname: Mima fullname: Mima, Shinji organization: Bioscience & Engineering Laboratory, Research & Development Management Headquarters, FUJIFILM Corporation, Japan – sequence: 3 givenname: Yuki surname: Imakura fullname: Imakura, Yuki organization: Bioscience & Engineering Laboratory, Research & Development Management Headquarters, FUJIFILM Corporation, Japan – sequence: 4 givenname: Toshihide surname: Miyashita fullname: Miyashita, Toshihide organization: Bioscience & Engineering Laboratory, Research & Development Management Headquarters, FUJIFILM Corporation, Japan – sequence: 5 givenname: Izumi surname: Ogura fullname: Ogura, Izumi organization: Bioscience & Engineering Laboratory, Research & Development Management Headquarters, FUJIFILM Corporation, Japan – sequence: 6 givenname: Tadanori surname: Yamada fullname: Yamada, Tadanori organization: Bioscience & Engineering Laboratory, Research & Development Management Headquarters, FUJIFILM Corporation, Japan – sequence: 7 givenname: Tomoya surname: Yasujima fullname: Yasujima, Tomoya organization: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan – sequence: 8 givenname: Hiroaki surname: Yuasa fullname: Yuasa, Hiroaki organization: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan – sequence: 9 givenname: Takahiro orcidid: 0000-0002-2452-9043 surname: Iwao fullname: Iwao, Takahiro email: tiwao@phar.nagoya-cu.ac.jp organization: Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan – sequence: 10 givenname: Tamihide surname: Matsunaga fullname: Matsunaga, Tamihide organization: Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan |
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| Keywords | Drug membrane permeability CYP3A4/5 activities Forskolin Human iPS cell-derived small intestinal epithelial cells Human primary small intestinal cells Differentiation Caco-2 cells |
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| SubjectTerms | 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 |
| Title | Pharmacokinetic functions of human induced pluripotent stem cell-derived small intestinal epithelial cells |
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