Simvastatin nanoliposome induces myocardial and hepatic toxicities due to its absorption enhancement in mice
Simvastatin nanoliposome induces myocardial and hepatic toxicities due to its absorption enhancement in mice
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辛伐他汀纳米脂质体因增强小鼠吸收而引起心肌和肝脏毒性
DOI：
10.1016/j.ajps.2019.02.002
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发表时间：
2019-05
影响因子：
10.2
通讯作者：
Qi Rong
中科院分区：
文献类型：
--
作者：
Tuerdi Nuerbiye;Anwaier Gulinigaer;Zhang Xing;Liu Shu;Shen Wanli;Liu Wen;Shen Qiang;Qi Rong
纳米脂质体是增加辛伐他汀(SMV)的溶解度和吸收，从而改善其治疗效果的一种有用的剂型。然而，SMV的体内毒性也可以随着吸收的增强而提高，这是SMV纳米脂质体(SMV-Lipo)临床应用的决定性因素，但到目前为止还没有系统的研究和报道。在这项研究中，SMV-Lipo在有无异丙肾上腺素存在和不存在的情况下对小鼠的器官毒性进行了评估，并与游离SMV进行了比较。结果表明，与游离SMV相比，SMV-Lipo25 mg/kg/d给药可导致严重的心肌毒性、基础肝毒性和更明显的肝损伤，丙氨酸氨基转移酶升高。此外，SMV-Lipo治疗组也观察到肌肉不良反应，而SMV组则未见。药代动力学研究表明，与游离SMV相比，SMV-Lipo显著提高了SMV的血药浓度，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50 mg/kg/d，产生与25 /kg/d的SMV-Lipo相当的血药浓度时，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SMV纳米脂质体制剂的吸收增强导致了比同等剂量的游离SMV更严重的心肌毒性。
Nanoliposome is a useful dosage form to increase solubility and absorption of simvastatin (SMV), and consequently improves its therapeutic effects. However,in vivotoxicity 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.
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DOI：
10.1016/s0735-1097(02)02030-2
发表时间：
2002-08-07
影响因子：
24
作者：
Pasternak, RC;Smith, SC;Lenfant, C
通讯作者：
Lenfant, C
DOI：
10.1007/bf00657505
发表时间：
1986-11
期刊：
Pflügers Archiv
影响因子：
--
作者：
K. Ullrich;F. Papavassiliou
通讯作者：
K. Ullrich;F. Papavassiliou
影响因子：
3.8
作者：
S. Rabkin;J. Kong
通讯作者：
S. Rabkin;J. Kong
影响因子：
5.8
作者：
Demyanets, S;Kaun, C;Wojta, J
通讯作者：
Wojta, J
G5 PAMAM树枝状聚合物与脂质体：辛伐他汀体外跨上皮转运和体内口服吸收的比较研究
影响因子：
5.4
作者：
Qi Rong;Zhang Heran;Xu Lu;Shen Wenwen;Chen Cong;Wang Chao;Cao Yini;Wang Yunan;van Dongen Mallory A.;He Bing;Wang Siling;Liu George;Holl Mark M. Banaszak;Zhang Qiang
通讯作者：
Zhang Qiang