Establishment of the novel experimental systems with human freshly-isolated intestinal tissues for the accurate prediction of intestinal drug absorption in humans
| Project/Area Number |
20H03402
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 47060:Clinical pharmacy-related
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| Research Institution | Kitasato University (2021-2022)
The University of Tokyo (2020) |
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Principal Investigator |
Kazuya Maeda 北里大学, 薬学部, 教授 (00345258)
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| Co-Investigator(Kenkyū-buntansha) |
小田 竜也 筑波大学, 医学医療系, 教授 (20282353)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2022: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2020: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
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| Keywords | 消化管吸収 / crypt / ヒト新鮮消化管 / 経細胞輸送 / Ussing chamber / 代謝酵素 / トランスポーター / バイオアベイラビリティ / 消化管吸収予測 / 薬物トランスポーター |
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| Outline of Research at the Start |
本来なら廃棄される手術残余のヒト新鮮消化管検体を利活用し、消化管組織を用いたUssing chamber法による透過性予測や消化管検体より単離したcrypt細胞（消化管細胞の前駆細胞）をtranswell上で消化管上皮細胞に分化させるin vitro実験系を構築し、創薬過程において、これまで適切な実験系がなかったヒトでの医薬品の消化管吸収の評価において、より予測精度の高い新規実験系およびin vitro試験の結果をin vivo消化管吸収率に理論的に変換する数理モデルとの統合システムを実現化する。
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| Outline of Final Research Achievements |
The prediction of intestinal absorption of drugs in humans does not always work well at the moment due to the large species differences in animal experiments and the differences in gene expression of metabolic enzymes and transporters between immortalized cells (e.g. Caco-2 cells) and human intact small intestine. In this study, we proposed the utilization of human surgical specimens as a novel experimental system for the prediction of drug intestinal absorption. The expression levels and functions of several metabolic enzymes and transporters were relatively maintained. A good prediction of the in vivo fraction of CYP3A substrate drugs which do not undergo intestinal absorption from the results of our experimental system can be realized. Our system can also be used to observe the regional differences in the absorption of compounds due to the uneven distribution of enzymes and transporters in the intestinal tract and induction of enzymes and transporters via transcriptional factors.
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| Academic Significance and Societal Importance of the Research Achievements |
経口薬の開発において、前臨床段階におけるヒト消化管吸収の定量的予測は重要な因子の一つである。しかしながら、これまでの手法では代謝酵素・トランスポーターの基質薬物に関しては予測性が良好ではない。本実験系は、ヒト消化管の吸収特性をよりよく再現可能な状況になっていることが見えてきた。よって最終的に我々の実験系は既存の実験系と置換しうるものであり、広く創薬現場における消化管吸収の予見性を高めるツールとして応用可能であると考えている。
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Report
(4 results)
Research Products
(31 results)
