| Project/Area Number |
16K15165
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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| Research Field |
Medical pharmacy
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| Research Institution | Tokyo University of Pharmacy and Life Science |
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Principal Investigator |
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| Research Collaborator |
INOUE Katsuhisa
KISHIMOTO Hisanao
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| Keywords | 消化管吸収 / 経口吸収 / 消化管 / 細胞培養 / 小腸モデル / 代謝酵素 / トランスポーター / 薬学 / 薬物動態学 / 培養細胞 / 代謝酵素・トランスポーター |
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| Outline of Final Research Achievements |
To develop intestinal villus model, a flow channel was built in the Transwell system, and Caco-2 cells was cultured under steady flow conditions. As a result, this culture method markedly increased TEER, which shows well-formed tight junctions compared to general culture conditions, suggesting an alteration of cellular morphology. On the other hand, mRNA expressions of MUC and CYP3A4 was decreased, and it was considered necessary to obtain alternative cell models. Therefore, next, we tried to establish a CYP3A4 stable expression system. Consequently, remarkable CYP3A4 expression and activity were confirmed in the cells. Change in this cellular morphology is expected by means of cell culture method with steady flow conditions. Furthermore, it is expected that this methodology contributes to improve the prediction efficiency of in vivo intestinal drug absorption.
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| Academic Significance and Societal Importance of the Research Achievements |
現在、医薬品開発の効率化を目的として、培養細胞や人工脂質膜を用いたin vitroでの薬物吸収性評価法が広く適用されている。しかし、いずれの評価系も実際の小腸における構造や環境を簡略化したシステムとして確立されているため、高精度な薬物吸収性予測を行うことは困難である。したがって、本研究の成果および展開として、よりリアルな小腸モデルの獲得が実現すれば、絨毛構造などに依存した機能性タンパク質発現、粘液分泌および有効表面積などを考慮できる高精度な薬物吸収性予測が可能となる。本細胞培養モデルの構築は、医薬品開発に大きく貢献することが期待されることから、本研究がもたらす成果の意義は極めて大きい。
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