2022 Fiscal Year Final Research Report

Establishment of the novel experimental systems with human freshly-isolated intestinal tissues for the accurate prediction of intestinal drug absorption in humans

Research Project

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Project/Area Number	20H03402
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Review Section	Basic Section 47060:Clinical pharmacy-related
Research Institution	Kitasato University (2021-2022) The University of Tokyo (2020)
Principal Investigator	Kazuya Maeda 北里大学, 薬学部, 教授 (00345258)
Co-Investigator(Kenkyū-buntansha)	小田竜也筑波大学, 医学医療系, 教授 (20282353)
Project Period (FY)	2020-04-01 – 2023-03-31
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
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.
Free Research Field	分子薬物動態学、生物薬剤学
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。