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Pharmacol Ther. 2017 Jul;175:1-16. doi: 10.1016/j.pharmthera.2017.02.029. Epub 2017 Feb 14.

Myotoxicity of statins: Mechanism of action.

Author information

1
Département de Pharmacologie, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada; Clinique de Nutrition, Métabolisme et Athérosclérose, Institut de Recherche Clinique de Montréal, 120, Avenue des Pins Ouest, Montréal, Québec, Canada. Electronic address: Patrick.du.souich@umontreal.ca.
2
Clinique de Nutrition, Métabolisme et Athérosclérose, Institut de Recherche Clinique de Montréal, 120, Avenue des Pins Ouest, Montréal, Québec, Canada.
3
Clinique de Prévention Cardiovasculaire, Institut de Recherche Clinique de Montréal, Canada; Département de nutrition, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada.

Abstract

Statins are effective drugs to reduce cardiovascular events secondary to dyslipidemia; however, they cause frequent undesirable side effects. The incidence of statin-induced myotoxicity (SIM) is presented by 7 to 29% of patients, depending upon the report. SIM may develop in presence of abnormally high concentrations of statins in the myocyte and/or in presence of muscular conditions that may predispose to SIM. High concentrations of statins in the myocyte may occur whenever the activity of liver influx membrane transporters, namely OATP1B1, of drug metabolizing enzymes, and of liver and muscular efflux transporters, MDR1 and BCRP, is reduced. In the muscle, conditions that may predispose to SIM include mitochondrial damage with disruption of the mitochondrial respiratory chain and decreased production of ATP, increase of ROS, and leak of cytochrome c and Ca2+. In the sarcoplasma, statins activate MAPK and diminish the RhoA/AKT/mTOR/PGC-1α pathway. All these effects contribute to activate apoptosis, proteolysis, and muscle remodeling. Moreover, in the sarcoplasma, statins can reduce the resting chloride channel conductance, as well as lactate efflux. These changes will be responsible of fatigue, cramps, myalgia and elevation of serum CK. To date, besides avoiding drug-drug interactions and alcohol consumption, and correcting hypothyroidism, two strategies could be useful to prevent/diminish SIM, e.g. gradual dose titration with statins less prone to produce SIM, and high supplements of vitamin D in subjects with low plasma concentrations of 25(OH) D3.

KEYWORDS:

Chloride channels; Lactate; Mechanism of action; Mitochondria; Muscle remodeling; Statins myopathy

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