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Drug Metab Dispos. 2018 Apr 3. pii: dmd.118.080374. doi: 10.1124/dmd.118.080374. [Epub ahead of print]

Generation of Intestinal Organoids Suitable for Pharmacokinetic Studies from Human Induced Pluripotent Stem Cells.

Author information

1
Graduate School of Pharmaceutical Sciences, Nagoya City University.
2
Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University.
3
Educational Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Nagoya City U.
4
Educational Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Nagoya City U tiwao@phar.nagoya-cu.ac.jp gckrmusliz@gmail.com i.o.music.0136@gmail.com tmatsu@phar.nagoya-cu.ac.jp.
5
Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University; tiwao@phar.nagoya-cu.ac.jp gckrmusliz@gmail.com i.o.music.0136@gmail.com tmatsu@phar.nagoya-cu.ac.jp.

Abstract

Intestinal organoids morphologically resemble intestinal tissues, and are expected to be used in both regenerative medicine and drug development studies, including pharmacokinetic studies. However, the pharmacokinetic properties of these organoids remain poorly characterized. In this study, we aimed to generate pharmacokinetically functional intestinal organoids from human induced pluripotent stem (iPS) cells. Human iPS cells were induced to differentiate into the hindgut and then seeded on EZSPHERE plates to generate uniform spheroids, and the floating spheroids were subsequently differentiated into intestinal organoids by using small-molecule compounds. Exposure to the small-molecule compounds potently increased the expression of intestinal markers and pharmacokinetic-related genes in the organoids, and the organoids also included various intestinal cells such as enterocytes, intestinal stem cells, goblet cells, enteroendocrine cells, Paneth cells, smooth muscle cells, and fibroblasts. Moreover, microvilli and tight junctions were observed in the organoids. Furthermore, we detected not only the expression of drug transporters, but also efflux transport activity through ABCB1/MDR1 (ATP-binding cassette, subfamily B, member 1/multi drug resistance 1), and the induction and activation of the drug-metabolizing enzyme cytochrome P450 (CYP) 3A4 by ligands of nuclear receptors. Our results demonstrated the successful generation of pharmacokinetically functional intestinal organoids from human iPS cells. Thus, these intestinal organoids could be used as a pharmacokinetic evaluation system in drug development studies.

KEYWORDS:

cytochrome P450; efflux transporters (P-gp, BCRP, MRP, MATE, BSEP, etc); organotypic models; pharmacokinetics; stem cells

PMID:
29615438
DOI:
10.1124/dmd.118.080374

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