title: Hyperlipidaemia alone and in combination with acidosis can increase the incidence and severity of statin-induced myotoxicity.
abstract: The association of lipophilic statins with plasma lipoproteins in the presence of disturbed acid-base balance can modify the pharmacokinetics and tissue distribution of these drugs, resulting in alteration in their efficacy and toxicity profiles. The purpose of this study is to elucidate the role of hyperlipidaemia alone or in combination with acidosis/alkalosis in the development and potentiation of statin-induced myotoxicity. Statins association with plasma lipoproteins was examined under conditions of physiological and altered pH levels. The effect of this association on cellular uptake and myotoxicity of statins was also assessed at different pH levels using C2C12 cells that overexpress lipoprotein lipase. Lipophilic simvastatin displayed considerable association with the non-polar lipoprotein fractions (triglyceride-rich lipoproteins and low-density lipoprotein). This association contributed to increased cellular uptake of simvastatin by C2C12 cells through lipoprotein lipase-mediated process, resulting in enhanced muscle toxicity in hyperlipidaemic conditions. Furthermore, a combination of low pH environment (representing acidosis) and hyperlipidaemia increased the association of simvastatin with plasma lipoproteins causing potentiation of cellular uptake and myotoxicity of this drug. Comorbidities such as hyperlipidaemia, especially when coincident with acidosis, can enhance statin-associated muscle toxicity, and therefore require extra caution by prescribing clinicians. Hydrophilic rather than lipophilic statins could be a preferable choice in this patient population.
authors.affiliation: Division of Medicinal Chemistry and Structural Biology, School of Pharmacy, University of Nottingham, Nottingham, UK.
authors.forename: Dhiaa A
authors.initials: DA
authors.lastname: Taha
authors.affiliation: Division of Medicinal Chemistry and Structural Biology, School of Pharmacy, University of Nottingham, Nottingham, UK; College of Pharmacy, University of Anbar, Anbar, Iraq.
authors.forename: Atheer
authors.initials: A
authors.lastname: Zgair
authors.affiliation: Division of Medicinal Chemistry and Structural Biology, School of Pharmacy, University of Nottingham, Nottingham, UK.
authors.forename: Jong Bong
authors.initials: JB
authors.lastname: Lee
authors.affiliation: Division of Molecular and Cellular Science, School of Pharmacy, University of Nottingham, Nottingham, UK.
authors.forename: Cornelia H
authors.initials: CH
authors.lastname: de Moor
authors.affiliation: Division of Molecular and Cellular Science, School of Pharmacy, University of Nottingham, Nottingham, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Barrett
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Kimberley D
authors.initials: KD
authors.lastname: Bruce
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Sungelo
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Eckel
authors.affiliation: Division of Medicinal Chemistry and Structural Biology, School of Pharmacy, University of Nottingham, Nottingham, UK. Electronic address: pavel.gershkovich@nottingham.ac.uk.
authors.forename: Pavel
authors.initials: P
authors.lastname: Gershkovich
mesh_terms: D000138:Acidosis / Q000378:metabolism*; D000328:Adult; D000818:Animals; D002460:Cell Line; D053298:Chylomicron Remnants / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D006949:Hyperlipidemias / Q000378:metabolism*; D008074:Lipoproteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008954:Models, Biological; D009135:Muscular Diseases / Q000139:chemically induced* / Q000378:metabolism; D017035:Pravastatin / Q000009:adverse effects* / Q000494:pharmacology; D019821:Simvastatin / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: D053298:Chylomicron Remnants; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008074:Lipoproteins; D019821:Simvastatin; D017035:Pravastatin
keywords: Acidosis; Chylomicrons; Hyperlipidemia; Lipoproteins; Myotoxicity; Pravastatin hydroxy acid (PubChem CID: 54687); Pravastatin lactone (PubChem CID: 9931182); Simvastatin hydroxy acid (PubChem CID: 64718); Simvastatin lactone (PubChem CID: 54454); Statins