P86 Establishment and characterization of a mouse model of rhabdomyolysis by coadministration of statin and fibrate

Katsuhiro Watanabe , Nagoya University Graduate School of Medicine, Nagoya, Japan
Shingo Oda , Nagoya University Graduate School of Medicine, Nagoya, Japan
Sho Akai , Nagoya University Graduate School of Medicine, Nagoya, Japan
Akiko Matsubara , Nagoya University Graduate School of Medicine, Nagoya, Japan
Tsuyoshi Yokoi , Drug Safety Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan
Rhabdomyolysis is characterized by elevation of plasma creatinine phosphokinase (CPK) levels and multiple organ disorders especially renal failure, and approximately 50% of acquired rhabdomyolysis is caused by pharmaceuticals. Statins are known to cause rhabdomyolysis, and its incidence rate has been reported to be about 10 times higher by coadministration of statin and fibrate. However, it has never been reported the establishment of drug-induced rhabdomyolysis animal model. In this study, a novel mouse model of statin and fibrate-induced rhabdomyolysis was established and clarified the mechanisms of its myotoxicity. We administered lovastatin (LV) and gemfibrozil (GF) with a glutathione synthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO), to C57BL/6J mice once daily for 3 days. The plasma levels of CPK, aspartate aminotransferase (AST), and miR-206 were prominently increased, and the levels of caspase 3/7 activity and oxidative stress-related factors, including heme oxygenase-1 (HO-1) and S100A9, were elevated in skeletal muscle. It is suggested that skeletal muscle toxicity involves apoptosis via oxidative stress. Upon histological examination, vacuoles were observed in renal proximal tubules, and renal mRNA levels of HO-1, Mt2 and lipocalin 2, renal injury marker, were markedly increased in BSO/LV/GF-administered mice. These results suggested that BSO/LV/GF-administered mice were affected with rhabdomyolysis. Moreover, this mouse model quantified adverse events of various statins. In conclusion, we successfully established a mouse model of rhabdomyolysis by coadministration of statin and fibrate, and this model could be a predictive test system for drug-induced skeletal muscle injury in pre-clinical drug development.