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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]

PMID: 37495742

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Project description:Background and aimsMetabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease that can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Though MASH is closely tied to metabolic risk factors, the underlying pathogenic mechanisms remain scarcely understood. Recent research has emphasized the importance of the gut-liver axis in its pathogenesis, an aspect less explored in human studies. Here, we investigated whether the duodenal epithelium of MASH patients could exhibit intrinsic dysfunctions.MethodsDuodenal epithelial organoids were generated from 16 MASH patients and 14 healthy controls. Biopsies and patient-derived organoid transcriptomes were then analyzed to evaluate if specific intestinal pathways were differentially modulated in MASH subjects. Functional assays were performed to assess the duodenal epithelial absorptive potential and barrier functionality.ResultsOrganoid formation efficiency was similar between control-derived duodenal epithelial organoids and MASH-derived duodenal epithelial organoids (MDEOs) (71% and 69%, respectively). Despite global heterogeneity in growth patterns, MDEOs frequently exhibited cystic spheroid morphology. MDEOs displayed altered digestive potential associated with reduced mature absorptive cell fate, but they retained their lipid metabolic capacity, possibly mediated by lipid oxidation in stem/progenitor cells. Additionally, MDEOs misexpressed components of tight and adherens junctions and desmosomes compared to controls. However, MDEOs maintained pore and leak pathway integrity, indicating that the duodenal epithelial barrier remained functionally preserved under tested conditions.ConclusionThis study provides evidence that the duodenal epithelium of MASH patients exhibits significant alterations in its nutrition-related and barrier functions. This study sheds light on the intricate dynamics of duodenal epithelial alterations in MASH, highlighting potential therapeutic avenues for restoring intestinal functions.

Dataset Information

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

Publications

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

Similar Datasets

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