The role of acid-base imbalance in statin-induced myotoxicity.
The role of acid-base imbalance in statin-induced myotoxicity.
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DOI：
10.1016/j.trsl.2016.03.015
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发表时间：
2016-08
期刊：
影响因子：
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通讯作者：
Gershkovich P
中科院分区：
文献类型：
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作者：
Taha DA;De Moor CH;Barrett DA;Lee JB;Gandhi RD;Hoo CW;Gershkovich P
酸碱平衡紊乱，如酸中毒和酒精中毒，有可能改变他汀类药物治疗的药理学和毒理学结果。他汀类药物通常用于患有多种合并症（如糖尿病、心血管疾病和肾脏疾病）的老年患者。这些患者有发生酸碱失衡的风险。在本研究中，已在生理缓冲液、人血浆和细胞培养基中研究了酸碱平衡紊乱对辛伐他汀和普伐他汀在内酯和羟基酸形式之间相互转化的影响，pH范围为6.8-7.8。这种相互转化对细胞摄取和他汀类药物的肌毒性的影响进行了评估，在体外使用C2 C12骨骼肌细胞相关的酸中毒，脱水，和生理pH值的条件下。结果表明，辛伐他汀和普伐他汀的内酯形式的转换为相应的羟基酸是强烈的pH值依赖性。在生理和碱性pH下，在37°C下孵育24小时后，大部分辛伐他汀内酯（SVL;分别为约87%和99%）和普伐他汀内酯（PVL;分别为约98%和99%）转化为活性羟基酸形式。在酸性pH下，转化发生的程度较低，导致更大比例的他汀类药物以更亲脂的内酯形式保留。然而，pH值的改变并不影响辛伐他汀和普伐他汀的羟基酸形式转化为相应的内酯。此外，酸中毒已被证明通过抑制肝微粒体酶活性来阻碍他汀类药物内酯形式的代谢。与亲水性辛伐他汀羟基酸、PVL和普伐他汀羟基酸相比，亲脂性SVL对未分化和分化的骨骼肌细胞具有更强的细胞毒性。在酸性条件下观察到他汀类药物的细胞毒性增强，这归因于更亲脂的内酯或未离子化羟基酸形式的细胞摄取增加。因此，我们的研究结果表明，与酸碱失衡相关的合并症可以在他汀类药物诱导的肌毒性的发展和增强中发挥重要作用。
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.