Relationship between simvastatin pharmacokinetics and muscle toxicity in male mice

Statins are highly effective in reducing plasma LDL-cholesterol but may be myotoxic. Since the relationship between statin exposure and myotoxicity is not clearly established, the current study aimed to compare blood and skeletal muscle concentrations with myotoxicity in male mice treated orally with 5, 10 and 25 mg/kg/day simvastatin for 3 weeks. After the first dose, simvastatin blood pharmacokinetics was dose-dependent, with exposures corresponding to humans treated with 80, 160 and 400 mg/day simvastatin. Skeletal muscle concentrations 24 h after the last dose of the three weeks-treatment period were dose-dependent with concentrations in the low nanomolar range. Simvastatin inhibited activation of key components of the insulin signaling pathway starting at 5 mg/kg/day whereas effects on physical performance and muscle strength were more accentuated at 10 than at 5 or 25 mg/kg/day. Simvastatin 25 mg/kg/day increased the SOD2 muscle protein expression. Simvastatin decreased gastrocnemius muscle total and reduced glutathione. In conclusion, oral administration of simvastatin from 5 to 25 mg/kg/day to mice showed linear pharmacokinetics and achieved blood concentrations equivalent to those obtained in humans treated with therapeutic to supratherapeutic doses. At 25 mg/kg simvastatin, myotoxicity is less accentuated than at 10 mg/kg, possibly due to induction of protective mechanisms.