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Research ArticleArticle

Characteristic Analysis of Intestinal Transport in Enterocyte-Like Cells Differentiated from Human Induced Pluripotent Stem Cells

Nao Kodama, Takahiro Iwao, Takahiro Katano, Kinya Ohta, Hiroaki Yuasa and Tamihide Matsunaga
Drug Metabolism and Disposition October 2016, 44 (10) 1662-1667; DOI: https://doi.org/10.1124/dmd.116.069336
Nao Kodama
Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan (N.K., T.I., T.M.), Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan (T.K., K.O., H.Y.)
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Takahiro Iwao
Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan (N.K., T.I., T.M.), Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan (T.K., K.O., H.Y.)
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Takahiro Katano
Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan (N.K., T.I., T.M.), Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan (T.K., K.O., H.Y.)
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Kinya Ohta
Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan (N.K., T.I., T.M.), Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan (T.K., K.O., H.Y.)
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Hiroaki Yuasa
Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan (N.K., T.I., T.M.), Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan (T.K., K.O., H.Y.)
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Tamihide Matsunaga
Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan (N.K., T.I., T.M.), Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan (T.K., K.O., H.Y.)
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Abstract

We previously demonstrated that differentiated enterocytes from human induced pluripotent stem (iPS) cells exhibited drug-metabolizing activities and cytochrome P450 CYP3A4 inducibility. The aim of this study was to apply human iPS cell–derived enterocytes in pharmacokinetic studies by investigating the characteristics of drug transport into enterocyte-like cells. Human iPS cells cultured on feeder cells were differentiated into endodermal cells using activin A. These endodermal-like cells were then differentiated into intestinal stem cells by fibroblast growth factor 2. Finally, epidermal growth factor and small-molecule compounds induced the maturation of the intestinal stem cell-like cells. After differentiation, we performed transepithelial electrical resistance (TEER) measurements, immunofluorescence staining, and transport studies. TEER values increased in a time-dependent manner and reached approximately 100 Ω × cm2. Efflux transport of Hoechst 33342, a substrate of breast cancer resistance protein (BCRP), was observed and inhibited by the BCRP inhibitor Ko143. The uptake of peptide transporter 1 substrate glycylsarcosine was also confirmed and suppressed when the temperature was lowered to 4°C. Using immunofluorescence staining, villin and Na+–K+ ATPase were expressed. These results suggest that human iPS cell–derived enterocytes had loose tight junctions, polarity, as well as uptake and efflux transport functions. In addition, the rank order of apparent membrane permeability coefficient (Papp) values of these test compounds across the enterocyte-like cell membrane corresponded to the fraction absorbance (Fa) values. Therefore, differentiated enterocytes from human iPS cells may provide a useful comprehensive evaluation model of drug transport and metabolism in the small intestine.

Footnotes

    • Received January 6, 2016.
    • Accepted July 13, 2016.
  • This work was supported, in part, by Grants-in-Aid from the Japan Society for the Promotion of Science [Grant 23390036, Grant 25860120, Grant 26293036]; Adaptable & Seamless Technology Transfer Program through Target-Driven R&D (A-STEP) of Japan Science and Technology Agency [AS262Z01122Q]; a grant of the Nakatomi Foundation [NF2014-32].

  • dx.doi.org/10.1124/dmd.116.069336.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (10)
Drug Metabolism and Disposition
Vol. 44, Issue 10
1 Oct 2016
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Research ArticleArticle

Intestinal Transport in Human iPS Cell–Derived Enterocytes

Nao Kodama, Takahiro Iwao, Takahiro Katano, Kinya Ohta, Hiroaki Yuasa and Tamihide Matsunaga
Drug Metabolism and Disposition October 1, 2016, 44 (10) 1662-1667; DOI: https://doi.org/10.1124/dmd.116.069336

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Research ArticleArticle

Intestinal Transport in Human iPS Cell–Derived Enterocytes

Nao Kodama, Takahiro Iwao, Takahiro Katano, Kinya Ohta, Hiroaki Yuasa and Tamihide Matsunaga
Drug Metabolism and Disposition October 1, 2016, 44 (10) 1662-1667; DOI: https://doi.org/10.1124/dmd.116.069336
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