HMG CoA reductase inhibition by Simvastatin gets rat β-Myosin heavy chain disappeared: A statin paradox (original) (raw)
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2007
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Anti-HMG-CoA reductase myopathy, an undesirable evolution of statin induced myopathy: a case report
Journal of Community Hospital Internal Medicine Perspectives, 2019
Statins are commonly used lipid lowering agents which play a pivotal role in reducing cardiovascular morbidity and mortality. Often well tolerated, these HMG-CoA reductase (HMGCR) inhibitors can sometimes cause severe muscle weakness and elevated creatinine kinase (CK) often labeled as statin intolerance or statin induced myopathy. These symptoms improve after discontinuation of the offending drug along with normalization of the enzyme levels. However, an entity called Immune Mediated Necrotizing Myopathy (IMNM), a type of autoimmune mediated myopathy, has been recognized and characterized in patients with history of statin exposure where there is persistence of proximal muscle weakness, CK elevation and myofiber necrosis can be seen on muscle biopsy even after stopping statins. With the increased use of statins, there seems to be a higher incidence of IMNM cases in recent years. Here we discuss a case of anti-HMG-CoA myopathy, one of the three recognized types of IMNM that has been more commonly associated with statin exposure and highly responsive to immunotherapy.
Simvastatin: In Vitro Metabolic Profiling of a Potent Competitive HMG-CoA Reductase Inhibitor
Separations
Simvastatin (SV) is a semisynthetic derivative of lovastatin (LV), which is biosynthetically produced from the fungus Aspergillus terreus and has a high log p value (log p = 4.39)and thus high hepatic extraction and high efficacy in controlling cholesterol synthesis. The current study was undertaken to investigate the metabolic profile of SV using various mass spectrometry (MS) platforms. Metabolic profiling was studied in in vitro models, rat liver microsomes (RLMs), and isolated perfused rat liver hepatocytes (RLHs) using both ion trap and triple quadruple LC–MS/MS systems. A total of 29 metabolites were identified. Among them, three types of SV-related phase-I metabolites, namely exomethylene simvastatin acid (exomethylene SVA), monohydroxy SVA, and dihydrodiol SVA, were identified as new in RLMs. No phase-II metabolites were identified while incubating with RLHs.
Biochemical and Biophysical Research Communications, 2015
HMG-CoA reductase (HMGCR) catalyzes the conversion of HMG-CoA to mevalonic acid (MVA); this is the rate-limiting enzyme of the mevalonate pathway that synthesizes cholesterol. Statins, HMGCR inhibitors, are widely used as cholesterol-reducing drugs. However, statin-induced myopathy is the most adverse side effect of statins. To eludicate the mechanisms underlying statin the myotoxicity and HMGCR function in the skeletal muscle, we developed the skeletal muscle-specific HMGCR knockout mice. Knockout mice exhibited postnatal myopathy with elevated serum creatine kinase levels and necrosis. Myopathy in knockout mice was completely rescued by the oral administration of MVA. These results suggest that skeletal muscle toxicity caused by statins is dependent on the deficiencies of HMGCR enzyme activity and downstream metabolites of the mevalonate pathway in skeletal muscles rather than the liver or other organs.