Clinical Pharmacology and Toxicology Research

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The acute effects of therapeutic concentrations of simvastatin lactone on mitochondrial respiratory capacity in human skeletal muscle: the LIFESTAT study

Author(s): Tine Lovsø Dohlmann*, Jørn Wulff Helge, Flemming Dela and Steen Larsen

Objectives: Simvastatin is a potent cholesterol lowering drug that may carry myalgia as a side effect. Whilst the underlying mechanism is unclear, statin therapy has been associated with impaired mitochondrial function. Two studies have differentiated between toxicity of simvastatin in its active acid and inactive lactone form, and found the inactive lactone form to be more toxic to myoblasts in vitro. Thus, the aim of this study was to investigate if therapeutic concentrations of simvastatin lactone in vitro impair mitochondrial respiration in skeletal muscle tissue, and if a dose dependent relationship exists.
Methods:
Muscle biopsies from 9 healthy adults were incubated with simvastatin corresponding to the maximal previously reported peak plasma concentration (Cmax), and in a 10 fold higher concentration to mimic intramuscular statin accumulation (0.1 μM and 1 μM, respectively). We measured mitochondrial maximal complex I and I+II linked respiration, which was succeeded by a stepwise simvastatin titration protocol to investigate a possible dose-dependent relationship.
Results: We found no effect on mitochondrial respiration using therapeutic concentrations of simvastatin (0.1 and 1 μM), but supratherapeutic concentrations yielded a dose-dependent inhibition of mitochondrial respiration.
Conclusion: These results implicate a possible toxic effect of simvastatin lactone on mitochondrial respiration, which may play a role in the development of statin induced myalgia, but only if the intramuscular accumulation of simvastatin lactone is high in myalgic statin users . This study emphasizes the need for investigating the degree of skeletal muscle statin accumulation in statin users experiencing myalgia.


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