Establishment of animal models and treatment methods for drug-induced rhabdomyolysis

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K15503
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Medical pharmacy
• Research Institution: Nagoya University
• Principal Investigator: Oda Shingo 名古屋大学, 医学系研究科, 特任助教 (10725534)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 医薬品副作用 / 横紋筋融解症 / 骨格筋障害 / 腎障害 / 動物モデル / グルタチオン / スタチン / フィブラート

Outline of Final Research Achievements

Rhabdomyolysis is characterized by elevation of plasma creatine phosphokinase (CPK) level, and multiple organ disorders, especially renal failure. In the statin and fibrate coadministration study, we found that coadministration of lovastatin and gemfibrozil under a glutathione (GSH)-depleted condition by L-buthionine-(S,R)-sulfoximine (BSO) for 3 days induced skeletal muscle injury with a CPK of 160,000 U/L. Coadministration of various statins and gemfibrozil to mice demonstrated a comparison of the myotoxic potential of statins. In the study for investigating the contribution of GSH to rhabdomyolysis, mice were treated with BSO twice daily for 7 days under a fasting condition. We found that the mice developed sever skeletal muscle injury. Importantly, renal injury secondary to rhabdomyolysis was observed. The mouse models established in this study would be useful in predicting myotoxic potential of drugs and in establishing remedies for acute kidney injury in drug development.

Free Research Field

医薬品安全性学

Academic Significance and Societal Importance of the Research Achievements

これまで汎用されてきたグリセロールを筋肉内投与する横紋筋融解症の動物モデルは、医薬品による横紋筋融解症の特性を必ずしも有しているわけではない。グルタチオン枯渇、フィブラート、及びスタチンの併用により作成した本動物モデルは、医薬品の骨格筋毒性ポテンシャル評価に有用であることが示唆され、医薬品開発における安全性評価に資すると考えられる。また、グルタチオン枯渇による横紋筋融解症/腎障害モデルは、横紋筋融解症に起因する新たな急性腎障害モデルの一つとなり得ると考えられる。