Simvastatin (MK 77333) 是一种具有口服

Simvastatin  (Synonyms: 辛伐他汀; MK 733)

Simvastatin (MK 77333) 是一种具有口服活性的 HMG-CoA 还原酶 (HMGCR) 竞争性抑制剂， K_i 为 0.2 nM。Simvastatin 可减少胆固醇的合成，降低血液中的胆固醇水平。Simvastatin 对癌细胞表现出抗增殖活性，并能诱导细胞凋亡 (apoptosis)。

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生物活性    
Simvastatin (MK 733) is a competitive inhibitor of HMG-CoA reductase with a Ki of 0.2 nM.

IC50 & Target    
Ki: 0.2 nM (HMG-CoA reductase)[1]

体外研究
(In Vitro)    
Simvastatin is an inactive drug precursor that has no drug activity itself and must be metabolized into its hydroxy acid form in the liver to function. In vitro experiments, it can be activated by sodium hydroxide (NaOH).
Simvastatin suppresses cholesterol synthesis in mouse L-M cell, rat H4II E cell, and human Hep G2 cell with IC50s of 19.3 nM, 13.3 nM and 15.6 nM, respectively[1].
Simvastatin causes a dose-dependent increase in serine 473 phosphorylation of Akt within 30 minutes, with maximal phosphorylation occurring at 1.0 µM[2].
Simvastatin (1.0 μM) enhances phosphorylation of the endogenous Akt substrate endothelial nitric oxide synthase (eNOS), inhibits serum-free media undergo apoptosis and accelerates vascular structure formation[2].
Simvastatin shows anti-inflammatory effects, reduces anti-CD3/anti-CD28 antibody-stimulated proliferation of PB-derived mononuclear cells and synovial fluid cells from rheumatoid arthritis blood, as well as IFN-γ release at 10 μM[3].
Simvastatin (10 μM) also blocks cell-mediated macrophage TNF-γ release induced via cognate interactions by appr 30%[3].
Simvastatin (5 μM) significantly reduces the expression of ABCA1 in astrocytes and neuroblastoma cells, the expression of apolipoprotein E in astrocytes, and increases cyclin-dependent kinase 5 and glycogen synthase kinase 3β expression in SK-N-SH cells[7].
Simvastatin has the ability to inhibit exosome release[10].
Simvastatin (32 and 64 μM; 24, 48, and 72 h) inhibits tumor cell growth, arrests in the G0/G1 phase[11].
Simvastatin (32 and 64 μM; 48 h) induces apoptosis in HepG2 and Huh7 cells[11].

Cell Proliferation Assay[11]

Cell Line:    HepG2 and Huh7 cells
Concentration:    32 and 64 μM
Incubation Time:    24, 48, and 72 hours
Result:    Inhibited tumor cell growth as compared to controls (ctrl, p<0.05).

体内研究
(In Vivo)    
Simvastatin suppresses the conversion of radiolabeled acetate to cholesterol with an IC50 of 0.2 mg/kg via p.o. administration[1]. Simvastatin (4 mg/day, p.o. for 13 weeks) returns the cholesterol-induced increases in total cholesterol, LDL-cholesterol and HDL-cholesterol to normal level in rabbits fed an atherogenci cholesterol-rich diet[4].
Simvastatin (6 mg/kg) increases LDL receptor-dependent binding and the number of hepatic LDL receptors in rabbits fed a diet containing 0.25% cholesterol[5].
Simvastatin (20 mg/kg/day) causes a 1.3-fold less macrophage content in lesions, and 2-fold less vascular cell adhesion molecule-1, interleukin-1beta, and tissue factor expression, companied by a 2.1-fold increases in lesional smooth muscle cell and collagen content in cynomolgus monkeys fed an atherogenic diet[6].
Simvastatin (oral gavage; 15 and 30 mg/kg; once daily; 14 d) treatment attenuats oxidative damage, TNF-a and IL-6 levels, and restores itochondrial enzyme complex activities[12].


Animal Model:    Male wistar rats with oxidative damage by Intrastriatal 6-OHDA administration[12]
Dosage:    15 and 30 mg/kg
Administration:    Oral gavage; 15 and 30 mg/kg; once daily; 14 days
Result:    Attenuated oxidative damage (reduced MDA, nitrite levels and restoration of reduced GSH) , attenuated TNF-a and IL-6 levels, and restored itochondrial enzyme complex activities as compared to 6-OHDA group.

分子量    
418.57

性状    
Solid

Formula    
C25H38O5

CAS 号    
79902-63-9

中文名称    
辛伐他汀；辛伐他丁

运输条件    
Room temperature in continental US; may vary elsewhere.

储存方式    
Powder    -20°C    3 years
4°C    2 years
In solvent    -80°C    6 months
-20°C    1 month
溶解性数据    
In Vitro: 
Ethanol : 100 mg/mL (238.91 mM; Need ultrasonic)

DMSO : ≥ 50 mg/mL (119.45 mM)

* "≥" means soluble, but saturation unknown.

配制储备液    
浓度溶剂体积质量    1 mg    5 mg    10 mg
1 mM    2.3891 mL    11.9454 mL    23.8909 mL
5 mM    0.4778 mL    2.3891 mL    4.7782 mL
10 mM    0.2389 mL    1.1945 mL    2.3891 mL
*
请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。
储备液的保存方式和期限：-80°C, 6 months; -20°C, 1 month。-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。

In Vivo:
请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照 In Vitro 方式配制澄清的储备液，再依次添加助溶剂：

——为保证实验结果的可靠性，澄清的储备液可以根据储存条件，适当保存；体内实验的工作液，建议您现用现配，当天使用； 以下溶剂前显示的百
分比是指该溶剂在您配制终溶液中的体积占比；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的方式助溶

1.
请依序添加每种溶剂： 50% PEG300    50% saline

Solubility: 10 mg/mL (23.89 mM); Suspended solution; Need ultrasonic

2.
请依序添加每种溶剂： 10% DMSO    40% PEG300    5% Tween-80    45% saline

Solubility: ≥ 2.5 mg/mL (5.97 mM); Clear solution

3.
请依序添加每种溶剂： 10% DMSO    90% (20% SBE-β-CD in saline)

Solubility: 2.5 mg/mL (5.97 mM); Suspended solution; Need ultrasonic

4.
请依序添加每种溶剂： 10% DMSO    90% corn oil

Solubility: ≥ 2.5 mg/mL (5.97 mM); Clear solution

5.
请依序添加每种溶剂： 10% EtOH    90% (20% SBE-β-CD in saline)

Solubility: ≥ 2.5 mg/mL (5.97 mM); Clear solution

6.
请依序添加每种溶剂： 10% EtOH    90% corn oil

Solubility: ≥ 2.5 mg/mL (5.97 mM); Clear solution

参考文献

[1]. Slater, E.E., et al. Mechanism of action and biological profile of HMG CoA reductase inhibitors. A new therapeutic alternative. Drugs, 1988. 36 Suppl 3: p. 72-82.  [Content Brief] [2]. Kureishi, Y., et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med, 2000. 6(9): p. 1004-10.  [Content Brief] [3]. Leung BP, et al. A novel anti-inflammatory role for simvastatin in inflammatory arthritis. J Immunol. 2003 Feb 1;170(3):1524-30.  [Content Brief] [4]. Kobayashi M, et al. Preventive effect of MK-733 (simvastatin), an inhibitor of HMG-CoA reductase, on hypercholesterolemia and atherosclerosis induced by cholesterol feeding in rabbits. Jpn J Pharmacol. 1989 Jan;49(1):125-33.  [Content Brief] [5]. Ishida F, et al. Comparative effects of simvastatin (MK-733) and CS-514 on hypercholesterolemia induced by cholesterol feeding in rabbits. Biochim Biophys Acta. 1990 Feb 23;1042(3):365-73.  [Content Brief] [6]. Sukhova GK, et al. Statins reduce inflammation in atheroma of nonhuman primates independent of effects on serum cholesterol. Arterioscler Thromb Vasc Biol. 2002 Sep 1;22(9):1452-8.  [Content Brief] [7]. Weijiang Dong, et al. Differential effects of simvastatin and CS-514 on expression of Alzheimer’s disease-related genes in human astrocytes and neuronal cells. J Lipid Res. 2009 Oct; 50(10): 2095-2102. [8]. Liu Z, et al. Pretreatment Donors after Circulatory Death with Simvastatin Alleviates Liver Ischemia Reperfusion Injury through a KLF2-Dependent Mechanism in Rat. Oxid Med Cell Longev. 2017;2017:3861914.  [Content Brief] [9]. Ifergan I, et al. Statins reduce human blood-brain barrier permeability and restrict leukocyte migration: relevance to multiple sclerosis. Ann Neurol. 2006 Jul;60(1):45-55.  [Content Brief] [10]. Zhang H, et al. Advances in the discovery of exosome inhibitors in cancer. J Enzyme Inhib Med Chem. 2020;35(1):1322-1330.  [Content Brief] [11]. Borna Relja, et al. Simvastatin inhibits cell growth and induces apoptosis and G0/G1 cell cycle arrest in hepatic cancer cells. Int J Mol Med. 2010 Nov;26(5):735-41.  [Content Brief] [12]. Anil Kumar, et al. Neuroprotective potential of atorvastatin and simvastatin (HMG-CoA reductase inhibitors) against 6-hydroxydopamine (6-OHDA) induced Parkinson-like symptoms. Brain Res. 2012 Aug 30;1471:13-22.  [Content Brief]