| Project/Area Number |
17H04103
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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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| Research Field |
Applied pharmacology
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| Research Institution | Kyushu University |
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Principal Investigator |
Ieiri Ichiro 九州大学, 九州大学病院, 教授 (60253473)
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| Co-Investigator(Kenkyū-buntansha) |
廣田 豪 九州大学, 薬学研究院, 准教授 (80423573)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000)
Fiscal Year 2019: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2018: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2017: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000)
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| Keywords | CYP3A4 / 個別化医療 / DNAメチル化 / バイオマーカー / メタボローム解析 / 臨床応用 / 薬剤反応性 |
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| Outline of Final Research Achievements |
Our previous studies suggest that the frequency of DNA methylation in human liver is responsible for individual differences in CYP3A4 expression. The frequency of DNA methylation varies in the cells derived from organs, even within the same subject. Biopsy of liver tissues is necessary to analyze the frequency of DNA methylation, but is difficult to perform due to its high invasiveness. In this study, a method for separating hepatocytes from peripheral blood by immunomagnetic separation has been established. Next, we performed a clinical study on the prediction of CYP3A4 activity based on DNA methylation analysis in healthy adults using our established methods. The purpose of this study was to determine the relationship between the frequency of DNA methylation in hepatocytes and the pharmacokinetics of midazolam, a known substrate of CYP3A4. The results of the clinical study suggest that DNA methylation can be applied as a marker for predicting individual CYP3A4 activity.
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| Academic Significance and Societal Importance of the Research Achievements |
臨床使用される大部分の医薬品の代謝に関与するCYP3A4の活性には、約20倍の個人差が認められることから、その活性予測は臨床・創薬の両面から切望されている。本試験により、末梢血から分離した肝細胞のDNAメチル化解析は、CYP3A4活性予測のマーカーとして応用可能であることが示唆された。本研究成果により確立した解析法は、臨床での応用を想定して検体の採取方法や採取量の構築を行った。今後の大規模試験の実施によるマーカーとしての感度と特異性の検証は重要であるが、社会実装が容易な解析法であることから、臨床・創薬への寄与が十分に期待でき社会的意義が大きいと考えられる。
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