Statin induced myotoxicity: The lactone forms are more potent than the acid forms in human skeletal muscle cells in vitro

• Published in: European journal of pharmaceutical sciences 2008-04, Vol.33 (4), p.317-325
• Main Authors: Skottheim, Ine Blankenberg, Gedde-Dahl, Ane, Hejazifar, Solmaz, Hoel, Kjersti, Åsberg, Anders
• Format: Article
• Language: English
• Subjects: Acid; Acids - chemistry; adverse events; atorvastatin; Atorvastatin Calcium; Cell Survival - drug effects; Cells, Cultured; Dose-Response Relationship, Drug; Drug Stability; drug-interactions; Farmaceutisk vetenskap; Fatty Acids, Monounsaturated - adverse effects; Fatty Acids, Monounsaturated - chemistry; Heptanoic Acids - adverse effects; Heptanoic Acids - chemistry; HMG-CoA reductase inhibitor; hmg-coa-reductase; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects; Hydroxymethylglutaryl-CoA Reductase Inhibitors - chemistry; In Vitro Techniques; Indoles - adverse effects; Indoles - chemistry; induced myopathy; inhibitors; Lactone; Lactones - chemistry; Microscopy, Fluorescence; Molecular Structure; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - pathology; Muscle, Skeletal - drug effects; Muscle, Skeletal - pathology; Myotoxicity; Pharmaceutical Sciences; plasma-concentrations; pravastatin; Pravastatin - adverse effects; Pravastatin - chemistry; Primary human skeletal muscle cells; proliferation; Pyrroles - adverse effects; Pyrroles - chemistry; Satellite Cells, Skeletal Muscle - drug effects; Satellite Cells, Skeletal Muscle - pathology; simvastatin; Simvastatin - adverse effects; Simvastatin - chemistry; Structure-Activity Relationship
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2007.12.009

Statins exist in both acid and lactone forms in vivo. High plasma levels of the lactone forms have been observed in patients with statin induced myopathy. In the present study, the hypothesis that lactone forms have a higher potency of inducing myotoxicity as compared to acid forms was investigated. Primary human skeletal muscle cells were incubated with increasing concentrations of lactone and acid forms of atorvastatin, fluvastatin, pravastatin and simvastatin. Following incubation, living myotubes were quantified by fluorescence staining. Atorvastatin lactone showed a 14-fold, fluvastatin lactone a 26-fold, pravastatin lactone a 23-fold, and simvastatin lactone a 37-fold higher potency to induce myotoxicity compared to their corresponding acid forms. Thus, for the four different statins the present study shows a significantly higher potency of the lactone forms, than the respective acid forms, to induce myotoxicity in human skeletal muscle cells in vitro. These results clearly indicate the need to differentiate between acid and lactone forms in future investigation of statin myotoxicity.