title: Statin induced myotoxicity: the lactone forms are more potent than the acid forms in human skeletal muscle cells in vitro.
abstract: 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.
authors.affiliation: School of Pharmacy, University of Oslo, Norway. i.b.skottheim@farmasi.uio.no
authors.forename: Ine Blankenberg
authors.initials: IB
authors.lastname: Skottheim
authors.forename: Ane
authors.initials: A
authors.lastname: Gedde-Dahl
authors.forename: Solmaz
authors.initials: S
authors.lastname: Hejazifar
authors.forename: Kjersti
authors.initials: K
authors.lastname: Hoel
authors.forename: Anders
authors.initials: A
authors.lastname: Asberg
mesh_terms: D000143:Acids / Q000737:chemistry; D000069059:Atorvastatin; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D005229:Fatty Acids, Monounsaturated / Q000009:adverse effects / Q000737:chemistry; D000077340:Fluvastatin; D006538:Heptanoic Acids / Q000009:adverse effects / Q000737:chemistry; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects* / Q000737:chemistry; D066298:In Vitro Techniques; D007211:Indoles / Q000009:adverse effects / Q000737:chemistry; D007783:Lactones / Q000737:chemistry; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000473:pathology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology; D017035:Pravastatin / Q000009:adverse effects / Q000737:chemistry; D011758:Pyrroles / Q000009:adverse effects / Q000737:chemistry; D032496:Satellite Cells, Skeletal Muscle / Q000187:drug effects* / Q000473:pathology; D019821:Simvastatin / Q000009:adverse effects / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000143:Acids; D005229:Fatty Acids, Monounsaturated; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D007783:Lactones; D011758:Pyrroles; D000077340:Fluvastatin; D000069059:Atorvastatin; D019821:Simvastatin; D017035:Pravastatin