The role of acid-base imbalance in statin-induced myotoxicity

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.

Hyperlipidaemia alone and in combination with acidosis can increase the incidence and severity of statin-induced myotoxicity

“…The selection of this range was based on extreme but clinically relevant disturbances in acid-base balance that are encountered in patients with long-term diuretics use (Tripathy, 2009), prolonged vomiting (Galla, 2000, diabetic ketoacidosis (Wathen and Starkey, 1986), lactic acidosis (Winocour et al, 1989), renal tubular acidosis (Kraut and Kurtz, 2005), hypovolemic shock (Zimmer, 2014), and ethylene glycol intoxication (Lundgaard, 2009). It should be noted that significant effects of milder plasma pH alterations on statin inter-conversion between lactone and hydroxy acid forms were also reported in our previous works (Taha et al, 2016 (Taha et al, 2016).…”

“…This is because acidosis, as we have previously demonstrated (Taha et al, 2016), increases the proportion of lipophilic lactone form of statins in the general circulation and skeletal muscle. This can contribute to statin-induced muscle toxicity by increasing the association of lactone form with plasma lipoproteins, and increasing the intracellular concentration of statins by LPLmediated mechanism.…”

“…All incubation experiments were carried out at physiological pH 7.4 in addition to pH levels that correspond to acidosis (pH 6.8) and alkalosis (pH 7.8) as describe previously (Taha et al, 2016). The selection of this range was based on extreme but clinically relevant disturbances in acid-base balance that are encountered in patients with long-term diuretics use (Tripathy, 2009), prolonged vomiting (Galla, 2000, diabetic ketoacidosis (Wathen and Starkey, 1986), lactic acidosis (Winocour et al, 1989), renal tubular acidosis (Kraut and Kurtz, 2005), hypovolemic shock (Zimmer, 2014), and ethylene glycol intoxication (Lundgaard, 2009).…”

“…Acidosis increases the proportion of lipophilic lactone form, promotes accumulation of statins in skeletal muscle cells and enhances statin-induced myotoxicity in vitro (Taha et al, 2016).…”

The Influences of SLCO1B1 and ABCB1 Genotypes on the Pharmacokinetics of Simvastatin, in Relation to CYP3A4 Inhibition

“…While an increased exposure to simvastatin acid (but not simvastatin) may appear to be the key pharmacokinetic mechanism behind the myo pathy among the SLCO1B1 c.521T>C carriers, less than one-fifth of these carriers will go on to develop this adverse effect [9] which suggests the presence of other nonpharmacokinetic contributing factors. A recent in vitro study suggests that decreased body fluid pH may play an important role in myotoxicity of simvastatin and simvastatin acid, particularly at higher drug concentrations [28], such are the cases in SLCO1B1 c.521T>C carriers and patients taking CYP3A4 inhibitors. It is known that diseases causing metabolic acidosis, such as diabetes and renal impairment are risk factors for simvastatin-inducedrhabdomyolysis [29].…”