Tuerdi Nuerbiye, Anwaier Gulinigaer, Zhang Xing, Liu Shu, Shen Wanli, Liu Wen, Shen Qiang, Qi Rong
School of Basic Medical Science, Shihezi University, Shihezi 832008, China.
Peking University Health Science Center, Institute of Cardiovascular Sciences, Peking University, Beijing 100191, China.
Asian J Pharm Sci. 2020 Jan;15(1):112-120. doi: 10.1016/j.ajps.2019.02.002. Epub 2019 May 25.
Nanoliposome is a useful dosage form to increase solubility and absorption of simvastatin (SMV), and consequently improves its therapeutic effects. However, toxicity of SMV could also be elevated accompanied by the absorption enhancement, which is a decisive factor for the clinical application of SMV nanoliposome (SMV-Lipo), but has not been studied systematically and reported so far. In this study, organ toxicity of SMV-Lipo was evaluated in mice in the presence and absence of isoproterenol and compared to those of free SMV. Results demonstrated that compared to free SMV, the SMV-Lipo administrated at an equal dose of 25 mg/kg/d led to severe myocardiotoxicity, hepatotoxicity at baseline and more pronounced liver injury with elevation of alanine aminotransferase. In addition, muscular adverse effect was also observed in SMV-Lipo treated group but not in SMV group. Pharmacokinetic studies revealed that compared to free SMV, the SMV-Lipo administration significantly improved the plasma SMV concentration, and the oral bioavailability was 6.5 times of free SMV. Notably, when the dosage of free SMV increased to 50 mg/kg/d, yielding the comparable plasma concentration as SMV-Lipo given at 25 mg/kg/d, the myocardiotoxicity was observed in free SMV treated mice as well, which further confirmed that the enhanced absorption of SMV by the nanoliposomal formulation resulted in more severe myocardiotoxicity than the equal dose of free SMV.
纳米脂质体是一种可提高辛伐他汀（SMV）溶解度和吸收度的有用剂型，从而改善其治疗效果。然而，随着吸收增强，SMV的毒性也可能升高，这是SMV纳米脂质体（SMV-Lipo）临床应用的决定性因素，但迄今为止尚未进行系统研究和报道。在本研究中，评估了在有和没有异丙肾上腺素的情况下SMV-Lipo对小鼠的器官毒性，并与游离SMV的毒性进行了比较。结果表明，与游离SMV相比，以25mg/kg/d的等剂量给予SMV-Lipo会导致严重的心肌毒性、基线时的肝毒性以及丙氨酸转氨酶升高导致更明显的肝损伤。此外，在SMV-Lipo治疗组中也观察到肌肉不良反应，而在SMV组中未观察到。药代动力学研究表明，与游离SMV相比，给予SMV-Lipo可显著提高血浆SMV浓度，口服生物利用度是游离SMV的6.5倍。值得注意的是，当游离SMV的剂量增加到50mg/kg/d，产生与以25mg/kg/d给予的SMV-Lipo相当的血浆浓度时，在游离SMV治疗的小鼠中也观察到了心肌毒性，这进一步证实了纳米脂质体制剂增强的SMV吸收导致比等剂量游离SMV更严重的心肌毒性。
