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.