| Project/Area Number |
18K14989
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 47060:Clinical pharmacy-related
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| Research Institution | Nihon Pharmaceutical University |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | Guanosine triphosphate / Tight junction / Mycophenolic acid / IMPDH inhibitor / Paracellular pathway / Sodium caprate / GTP / ミコフェノール酸 / グアノシン / 消化管吸収 / Tight Junction |
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| Outline of Final Research Achievements |
In this study, we focused on the possibility of regulating the tight junction (TJ) by altering intracellular guanosine triphosphate (GTP) levels as a novel mechanism for regulating drug absorption from the gastrointestinal tract. Mycophenolic acid (MPA), an inhibitor of Inosine 5'-monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in the de novo pathway of GTP production in cells, reduced intracellular GTP levels and affected TJ. The trans-epithelial electrical resistance (TEER), an indicator of TJ opening, increased in a concentration- and exposure time-dependent manner of MPA. On the other hand, the amount of intracellular ATP was not affected by MPA exposure.
Although we were unable to clarify the detail mechanism of TJ enhancement by MPA exposure, we found the possibility of a novel system for regulating gastrointestinal mucosal permeability by regulating intracellular GTP levels.
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| Academic Significance and Societal Importance of the Research Achievements |
薬物の消化管吸収は、経口投与製剤の効果発現のための最初の障壁であり最大の障壁ともいえる。現在、難溶性・難吸収性の薬物が増加していることから、消化管における吸収制御技術の向上は経口投与製剤の開発および使用において極めて重要な課題である。これまでに薬物の吸収促進剤を含めた吸収制御に関する研究は数多くなされてきているが、臨床応用に至った例は数少ない。したがって、消化管吸収における吸収制御技術を目的とし、その可能性を見出すことができた本研究は、社会的ニーズが高い研究であるといえる。
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