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


ABSTRACT: 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.

SUBMITTER: Tanaka K 

PROVIDER: S-EPMC10372144 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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

Tanaka Kai K   Kawai Shigeto S   Fujii Etsuko E   Yano Masumi M   Miyayama Takashi T   Nakano Kiyotaka K   Terao Kimio K   Suzuki Masami M  

Scientific reports 20230726 1


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 organ  ...[more]

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