Statin induced myotoxicity:: The lactone forms are more potent than the acid forms in human skeletal muscle cells in vitro
Statin induced myotoxicity:: The lactone forms are more potent than the acid forms in human skeletal muscle cells in vitro
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DOI：
10.1016/j.ejps.2007.12.009
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发表时间：
2008-04-23
影响因子：
4.6
通讯作者：
Asbery, Anders
中科院分区：
文献类型：
--
作者：
Skottheim, Ine Blankenbery;Gedde-Dahl, Ane;Asbery, Anders
他汀类药物在体内以酸和内酯的形式存在。在他汀类药物诱导的肌病患者中观察到高水平的内酯形式。在目前的研究中，内酯形式与酸性形式相比具有更高的诱导肌肉毒性的效力的假设被调查。原代人骨骼肌细胞与浓度增加的内酯和酸性形式的阿托伐他汀、氟伐他汀、普伐他汀和辛伐他汀孵育。孵育后，用荧光染色对活的肌管进行定量。与相应的酸性形式相比，阿托伐他汀内酯显示出14倍，氟伐他汀内酯是26倍，普伐他汀内酯是23倍，辛伐他汀内酯是37倍。因此，对于这四种不同的他汀类药物，本研究表明内酯形式比各自的酸形式在体外诱导人骨骼肌细胞肌毒性的效力要高得多。这些结果清楚地表明，在未来他汀类药物的肌毒性研究中，有必要区分酸性和内酯形式。(C)2008爱思唯尔B.V.保留所有权利。
Statins exist in both acid and lactone forms in vivo. High plasma levels of the lactone forms have been observed in patients with statin induced myopathy. In the present study, the hypothesis that lactone forms have a higher potency of inducing myotoxicity as compared to acid forms was investigated. Primary human skeletal muscle cells were incubated with increasing concentrations of lactone and acid forms of atorvastatin, fluvastatin, pravastatin and simvastatin. Following incubation, living myotubes were quantified by fluorescence staining. Atorvastatin lactone showed a 14-fold, fluvastatin lactone a 26-fold, pravastatin lactone a 23-fold, and simvastatin lactone a 37-fold higher potency to induce myotoxicity compared to their corresponding acid forms. Thus, for the four different statins the present study shows a significantly higher potency of the lactone forms, than the respective acid forms, to induce myotoxicity in human skeletal muscle cells in vitro. These results clearly indicate the need to differentiate between acid and lactone forms in future investigation of statin myotoxicity. (C) 2008 Elsevier B.V. All rights reserved.