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Development of rat duodenal monolayer model with effective barrier function from rat organoids for ADME assay

The in-depth analysis of the ADME profiles of drug candidates using in vitro models is essential for drug development since a drug’s exposure in humans depends on its ADME properties. In contrast to efforts in developing human in vitro absorption models, only a limited number of studies have explore...

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Autores principales: Tanaka, Kai, Kawai, Shigeto, Fujii, Etsuko, Yano, Masumi, Miyayama, Takashi, Nakano, Kiyotaka, Terao, Kimio, Suzuki, Masami
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10372144/
https://www.ncbi.nlm.nih.gov/pubmed/37495742
http://dx.doi.org/10.1038/s41598-023-39425-7
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author Tanaka, Kai
Kawai, Shigeto
Fujii, Etsuko
Yano, Masumi
Miyayama, Takashi
Nakano, Kiyotaka
Terao, Kimio
Suzuki, Masami
author_facet Tanaka, Kai
Kawai, Shigeto
Fujii, Etsuko
Yano, Masumi
Miyayama, Takashi
Nakano, Kiyotaka
Terao, Kimio
Suzuki, Masami
author_sort Tanaka, Kai
collection PubMed
description The in-depth analysis of the ADME profiles of drug candidates using in vitro models is essential for drug development since a drug’s exposure in humans depends on its ADME properties. In contrast to efforts in developing human in vitro absorption models, only a limited number of studies have explored models using rats, the most frequently used species in in vivo DMPK studies. In this study, we developed a monolayer model with an effective barrier function for ADME assays using rat duodenal organoids as a cell source. At first, we developed rat duodenal organoids according to a previous report, but they were not able to generate a confluent monolayer. Therefore, we modified organoid culture protocols and developed cyst-enriched organoids; these strongly promoted the formation of a confluent monolayer. Furthermore, adding valproic acid to the culture accelerated the differentiation of the monolayer, which possessed an effective barrier function and apicobasal cell polarity. Drug transporter P-gp function as well as CYP3A activity and nuclear receptor function were confirmed in the model. We expect our novel monolayer model to be a useful tool for elucidating drug absorption processes in detail, enabling the development of highly absorbable drugs.
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spelling pubmed-103721442023-07-28 Development of rat duodenal monolayer model with effective barrier function from rat organoids for ADME assay Tanaka, Kai Kawai, Shigeto Fujii, Etsuko Yano, Masumi Miyayama, Takashi Nakano, Kiyotaka Terao, Kimio Suzuki, Masami Sci Rep Article The in-depth analysis of the ADME profiles of drug candidates using in vitro models is essential for drug development since a drug’s exposure in humans depends on its ADME properties. In contrast to efforts in developing human in vitro absorption models, only a limited number of studies have explored models using rats, the most frequently used species in in vivo DMPK studies. In this study, we developed a monolayer model with an effective barrier function for ADME assays using rat duodenal organoids as a cell source. At first, we developed rat duodenal organoids according to a previous report, but they were not able to generate a confluent monolayer. Therefore, we modified organoid culture protocols and developed cyst-enriched organoids; these strongly promoted the formation of a confluent monolayer. Furthermore, adding valproic acid to the culture accelerated the differentiation of the monolayer, which possessed an effective barrier function and apicobasal cell polarity. Drug transporter P-gp function as well as CYP3A activity and nuclear receptor function were confirmed in the model. We expect our novel monolayer model to be a useful tool for elucidating drug absorption processes in detail, enabling the development of highly absorbable drugs. Nature Publishing Group UK 2023-07-26 /pmc/articles/PMC10372144/ /pubmed/37495742 http://dx.doi.org/10.1038/s41598-023-39425-7 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Tanaka, Kai
Kawai, Shigeto
Fujii, Etsuko
Yano, Masumi
Miyayama, Takashi
Nakano, Kiyotaka
Terao, Kimio
Suzuki, Masami
Development of rat duodenal monolayer model with effective barrier function from rat organoids for ADME assay
title Development of rat duodenal monolayer model with effective barrier function from rat organoids for ADME assay
title_full Development of rat duodenal monolayer model with effective barrier function from rat organoids for ADME assay
title_fullStr Development of rat duodenal monolayer model with effective barrier function from rat organoids for ADME assay
title_full_unstemmed Development of rat duodenal monolayer model with effective barrier function from rat organoids for ADME assay
title_short Development of rat duodenal monolayer model with effective barrier function from rat organoids for ADME assay
title_sort development of rat duodenal monolayer model with effective barrier function from rat organoids for adme assay
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10372144/
https://www.ncbi.nlm.nih.gov/pubmed/37495742
http://dx.doi.org/10.1038/s41598-023-39425-7
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