Development of a novel gut microphysiological system that facilitates assessment of drug absorption kinetics in gut
Abstract There is an urgent need for novel methods that can accurately predict intestinal absorption of orally administered drugs in humans. This study aimed to evaluate the potential of a novel gut microphysiological system (MPS), gut MPS/Fluid3D-X, to assess the intestinal absorption of drugs in h...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-12-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-80946-6 |
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| author | Tomoki Imaoka Reiko Onuki-Nagasaki Hiroshi Kimura Kempei Tai Mitsuharu Ishii Ayaka Nozue Ikuko Kaisaki Misa Hoshi Kengo Watanabe Kazuya Maeda Takashi Kamizono Takahiro Yoshioka Takashi Fujimoto Taku Satoh Hiroko Nakamura Osamu Ando Hiroyuki Kusuhara Yuzuru Ito |
| author_facet | Tomoki Imaoka Reiko Onuki-Nagasaki Hiroshi Kimura Kempei Tai Mitsuharu Ishii Ayaka Nozue Ikuko Kaisaki Misa Hoshi Kengo Watanabe Kazuya Maeda Takashi Kamizono Takahiro Yoshioka Takashi Fujimoto Taku Satoh Hiroko Nakamura Osamu Ando Hiroyuki Kusuhara Yuzuru Ito |
| author_sort | Tomoki Imaoka |
| collection | DOAJ |
| description | Abstract There is an urgent need for novel methods that can accurately predict intestinal absorption of orally administered drugs in humans. This study aimed to evaluate the potential of a novel gut microphysiological system (MPS), gut MPS/Fluid3D-X, to assess the intestinal absorption of drugs in humans. The gut MPS/Fluid3D-X model was constructed using a newly developed flow-controllable and dimethylpolysiloxane-free MPS device (Fluid3D-X®). Human induced pluripotent stem cells-derived small intestinal epithelial cells were employed in this model, which exhibited key characteristics of the human absorptive epithelial cells of the small intestine, including the expression of key gene transcripts responsible for drug transport and metabolism, and the presence of dome-like protrusions in the primary intestinal epithelium under air-liquid interface culture conditions. Functional studies of transporters in the constructed model demonstrated basal-to-apical directional transport of sulfasalazine and quinidine, substrates of the active efflux transporters breast cancer resistance protein and P-glycoprotein, respectively, which were diminished by inhibitors. Furthermore, a cytochrome P450 (CYP) 3A inhibitor increased the apical-to-basal transport of midazolam, a typical CYP3A4 substrate, and reduced metabolite formation. These results suggest that gut MPS/Fluid3D-X has the potential to assess the intestinal absorption of small-molecule drugs. |
| format | Article |
| id | doaj-art-6a1c420ff7d34af0a6f6855d7e06fa8a |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-6a1c420ff7d34af0a6f6855d7e06fa8a2025-08-20T02:30:56ZengNature PortfolioScientific Reports2045-23222024-12-0114111210.1038/s41598-024-80946-6Development of a novel gut microphysiological system that facilitates assessment of drug absorption kinetics in gutTomoki Imaoka0Reiko Onuki-Nagasaki1Hiroshi Kimura2Kempei Tai3Mitsuharu Ishii4Ayaka Nozue5Ikuko Kaisaki6Misa Hoshi7Kengo Watanabe8Kazuya Maeda9Takashi Kamizono10Takahiro Yoshioka11Takashi Fujimoto12Taku Satoh13Hiroko Nakamura14Osamu Ando15Hiroyuki Kusuhara16Yuzuru Ito17Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., LtdInstitute of Life and Environmental Sciences, University of TsukubaMicro/Nano Technology Center, Tokai UniversityGraduate School of Pharmaceutical Sciences, The University of TokyoInstitute of Life and Environmental Sciences, University of TsukubaInstitute of Life and Environmental Sciences, University of TsukubaGraduate School of Pharmaceutical Sciences, The University of TokyoDrug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., LtdDrug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., LtdKitasato University School of PharmacyTokyo Ohka Kogyo Co. LtdTokyo Ohka Kogyo Co. LtdTokyo Ohka Kogyo Co. LtdInstitute of Life and Environmental Sciences, University of TsukubaMicro/Nano Technology Center, Tokai UniversityInstitute of Life and Environmental Sciences, University of TsukubaGraduate School of Pharmaceutical Sciences, The University of TokyoInstitute of Life and Environmental Sciences, University of TsukubaAbstract There is an urgent need for novel methods that can accurately predict intestinal absorption of orally administered drugs in humans. This study aimed to evaluate the potential of a novel gut microphysiological system (MPS), gut MPS/Fluid3D-X, to assess the intestinal absorption of drugs in humans. The gut MPS/Fluid3D-X model was constructed using a newly developed flow-controllable and dimethylpolysiloxane-free MPS device (Fluid3D-X®). Human induced pluripotent stem cells-derived small intestinal epithelial cells were employed in this model, which exhibited key characteristics of the human absorptive epithelial cells of the small intestine, including the expression of key gene transcripts responsible for drug transport and metabolism, and the presence of dome-like protrusions in the primary intestinal epithelium under air-liquid interface culture conditions. Functional studies of transporters in the constructed model demonstrated basal-to-apical directional transport of sulfasalazine and quinidine, substrates of the active efflux transporters breast cancer resistance protein and P-glycoprotein, respectively, which were diminished by inhibitors. Furthermore, a cytochrome P450 (CYP) 3A inhibitor increased the apical-to-basal transport of midazolam, a typical CYP3A4 substrate, and reduced metabolite formation. These results suggest that gut MPS/Fluid3D-X has the potential to assess the intestinal absorption of small-molecule drugs.https://doi.org/10.1038/s41598-024-80946-6 |
| spellingShingle | Tomoki Imaoka Reiko Onuki-Nagasaki Hiroshi Kimura Kempei Tai Mitsuharu Ishii Ayaka Nozue Ikuko Kaisaki Misa Hoshi Kengo Watanabe Kazuya Maeda Takashi Kamizono Takahiro Yoshioka Takashi Fujimoto Taku Satoh Hiroko Nakamura Osamu Ando Hiroyuki Kusuhara Yuzuru Ito Development of a novel gut microphysiological system that facilitates assessment of drug absorption kinetics in gut Scientific Reports |
| title | Development of a novel gut microphysiological system that facilitates assessment of drug absorption kinetics in gut |
| title_full | Development of a novel gut microphysiological system that facilitates assessment of drug absorption kinetics in gut |
| title_fullStr | Development of a novel gut microphysiological system that facilitates assessment of drug absorption kinetics in gut |
| title_full_unstemmed | Development of a novel gut microphysiological system that facilitates assessment of drug absorption kinetics in gut |
| title_short | Development of a novel gut microphysiological system that facilitates assessment of drug absorption kinetics in gut |
| title_sort | development of a novel gut microphysiological system that facilitates assessment of drug absorption kinetics in gut |
| url | https://doi.org/10.1038/s41598-024-80946-6 |
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