Quantitative model analysis of biomarkers to predict pharmacokinetic changes associated with lifestyle-related diseases

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03405
• 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: Kyushu University
• Principal Investigator: Hirota Takeshi 九州大学, 大学病院, 准教授/副薬剤部長 (80423573)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 高血糖 / 薬物トランスポーター

Outline of Final Research Achievements

The expression levels of drug transporters, which play an important role in pharmacokinetics, are reportedly altered by diabetes. Changes in gene expression based on lifestyle differences depend mainly on epigenetic mechanisms. In this study, therefore, we focused on the RNA methylation mechanism, N6-methyladenosine (m6A) modification. The effect of high glucose concentrations on m6A modification was analyzed in vitro. As a result, the expression of Fat mass and obesity-associated, a demethylase, was significantly reduced under high glucose conditions. Comprehensive analysis revealed variations in m6A modification in organic anion transporter. We identified miRNAs that control the expression of FTO. Using circulating miRNAs as biomarkers is expected to lead to the development of personalized medicine.

Free Research Field

薬物動態学

Academic Significance and Societal Importance of the Research Achievements

糖尿病患者は様々な疾病の発症率が高く、服用薬が多様化している。本研究にて、高血糖によりRNAメチル化が変動し、その発現量が上昇したorganic anion transporterは、幅広い薬物を基質とする。糖尿病合併症の一種である脂質異常症の治療薬であるスタチンは、一部のorganic anion transporter によって輸送される。同遺伝子の発現変動は、薬効に影響する可能性が考えられる。以上より、高濃度グルコース条件下における薬物トランスポーター発現制御機構を理解することは、多様な薬物を服用する糖尿病患者に対して、適切な投与設計を行う上で有用な情報となり得る。