title: Mechanisms and assessment of statin-related muscular adverse effects.
abstract: Statin-associated muscular adverse effects cover a wide range of symptoms, including asymptomatic increase of creatine kinase serum activity and life-threatening rhabdomyolysis. Different underlying pathomechanisms have been proposed. However, a unifying concept of the pathogenesis of statin-related muscular adverse effects has not emerged so far. In this review, we attempt to categorize these mechanisms along three levels. Firstly, among pharmacokinetic factors, it has been shown for some statins that inhibition of cytochrome P450-mediated hepatic biotransformation and hepatic uptake by transporter proteins contribute to an increase of systemic statin concentrations. Secondly, at the myocyte membrane level, cell membrane uptake transporters affect intracellular statin concentrations. Thirdly, at the intracellular level, inhibition of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase results in decreased intracellular concentrations of downstream metabolites (e.g. selenoproteins, ubiquinone, cholesterol) and alteration of gene expression (e.g. ryanodine receptor 3, glycine amidinotransferase). We also review current recommendations for prescribers.
authors: Division of General Practice, University Hospital Tübingen, Tübingen, D-72074, Germany.
authors: Dirk
authors: D
authors: Moßhammer
authors: Elke
authors: E
authors: Schaeffeler
authors: Matthias
authors: M
authors: Schwab
authors: Klaus
authors: K
authors: Mörike
mesh_terms: D000818:Animals; D003402:Creatine Kinase / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D032342:Muscle Cells / Q000378:metabolism; D009135:Muscular Diseases / Q000139:chemically induced* / Q000503:physiopathology; D012206:Rhabdomyolysis / Q000139:chemically induced* / Q000503:physiopathology
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D003577:Cytochrome P-450 Enzyme System; D003402:Creatine Kinase
keywords: adverse effects; efflux transporters; myopathy; organic anion transporters; rhabdomyolysis; statins