1. The role of acid-base imbalance in statin-induced myotoxicity
- Author
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Dhiaa A, Taha, Cornelia H, De Moor, David A, Barrett, Jong Bong, Lee, Raj D, Gandhi, Chee Wei, Hoo, and Pavel, Gershkovich
- Subjects
Simvastatin ,Cell Membrane Permeability ,Time Factors ,MRP, multiresistant protein ,MTT, thiazolyl blue tetrazolium bromide ,OATP, organic anionic transporting polypeptide ,RSD, relative standard deviation ,Acid-Base Imbalance ,Muscle Development ,Mice ,Plasma ,IS, internal standard ,Chromatography, High Pressure Liquid ,Pravastatin ,Cell Death ,LDH, lactate dehydrogenase ,Hydrolysis ,Muscles ,LOV-A, lovastatin hydroxy acid ,Cell Differentiation ,Hydrogen-Ion Concentration ,mRNA, messenger RNA ,PVA, pravastatin hydroxy acid ,Microsomes, Liver ,lipids (amino acids, peptides, and proteins) ,Original Article ,PVL, pravastatin lactone ,MHC, myosin heavy chain ,Tbp, TATA box-binding protein ,LOV-L, lovastatin lactone ,RE, relative error ,NA, nonapplicable ,LLOQ, lower limit of quantification ,Gapdh, glyceraldehyde-3-phosphate dehydrogenase ,HQC, high concentration quality control ,LQC, low concentration quality control ,Cell Line ,cDNA, complementary DNA ,PBS, phosphate buffer saline ,Animals ,Humans ,Rps12, ribosomal protein S12 ,SVA, simvastatin hydroxy acid ,L-Lactate Dehydrogenase ,Hprt, hypoxanthine phosphoribosyl transferase ,nutritional and metabolic diseases ,Membrane Transport Proteins ,Culture Media ,SVL, simvastatin lactone ,MQC, medium concentration quality control ,DMEM, Dulbecco's modified eagle medium ,Ct, cycle threshold ,Hydroxymethylglutaryl-CoA Reductase Inhibitors - Abstract
Disturbances in acid-base balance, such as acidosis and alkalosis, have potential to alter the pharmacologic and toxicologic outcomes of statin therapy. Statins are commonly prescribed for elderly patients who have multiple comorbidities such as diabetes mellitus, cardiovascular, and renal diseases. These patients are at risk of developing acid-base imbalance. In the present study, the effect of disturbances in acid-base balance on the interconversion of simvastatin and pravastatin between lactone and hydroxy acid forms have been investigated in physiological buffers, human plasma, and cell culture medium over pH ranging from 6.8–7.8. The effects of such interconversion on cellular uptake and myotoxicity of statins were assessed in vitro using C2C12 skeletal muscle cells under conditions relevant to acidosis, alkalosis, and physiological pH. Results indicate that the conversion of the lactone forms of simvastatin and pravastatin to the corresponding hydroxy acid is strongly pH dependent. At physiological and alkaline pH, substantial proportions of simvastatin lactone (SVL; ∼87% and 99%, respectively) and pravastatin lactone (PVL; ∼98% and 99%, respectively) were converted to the active hydroxy acid forms after 24 hours of incubation at 37°C. At acidic pH, conversion occurs to a lower extent, resulting in greater proportion of statin remaining in the more lipophilic lactone form. However, pH alteration did not influence the conversion of the hydroxy acid forms of simvastatin and pravastatin to the corresponding lactones. Furthermore, acidosis has been shown to hinder the metabolism of the lactone form of statins by inhibiting hepatic microsomal enzyme activities. Lipophilic SVL was found to be more cytotoxic to undifferentiated and differentiated skeletal muscle cells compared with more hydrophilic simvastatin hydroxy acid, PVL, and pravastatin hydroxy acid. Enhanced cytotoxicity of statins was observed under acidic conditions and is attributed to increased cellular uptake of the more lipophilic lactone or unionized hydroxy acid form. Consequently, our results suggest that comorbidities associated with acid-base imbalance can play a substantial role in the development and potentiation of statin-induced myotoxicity.
- Published
- 2015