Simvastatin (MK 733)

Biological Activity

Simvastatin (MK-0733, MK 733) is a competitive inhibitor of HMG-CoA reductase with Ki of 0.1-0.2 nM in cell-free assays. Simvastatin induces ferroptosis, mitophagy, autophagy and apoptosis. Simvastatin inhibits exosome release.

Prior to use in cell assays, Simvastatin needs to be activated by NaOH in EtOH treatment. Simvastatin inhibits cholesterol synthesis in mouse L-M cell (fibroblast), rat H4II E cell (liver), and human Hep G2 cell (liver) with IC50 of 19.3 nM, 13.3 nM and 15.6 nM, respectively. Simvastatin treatment leads to a dose-dependent increase in serine 473 phosphorylation of Akt within 30 minutes, with maximal phosphorylation occurring at 1.0 µM.

In vivo, Simvastatin orally administration inhibits the conversion of radiolabeled acetate to cholesterol with IC50 of 0.2 mg/kg. Simvastatin (4 mg/day) orally administration for 13 weeks to rabbits fed an atherogenci cholesterol-rich diet, returns the cholesterol-induced increases in total cholesterol, LDL-cholesterol and HDL-cholesterol to normal level. Simvastatin (6 mg/kg) produces an increase in LDL receptor-dependent binding and increases the number of hepatic LDL receptors in rabbits fed a diet containing 0.25% cholesterol.

Activation of simvastatin

Simvastatin needs to be activated by opening of the lactone ring before use in cell culture. Briefly, eight milligrams of simvastatin (0.019 mM) were dissolved in 0.2 ml of 100% ethanol, with subsequent addition of 0.3 ml of 0.1 N NaOH. The solution was heated at 50°C for 2 h in a sand bath and then neutralized with HCl to pH 7.2. The resulting solution was brought to a final volume (1 ml) with distilled water, and aliquots were stored at −80°C until use.

Product Citations

• 

  J Funct Foods. 2022 Mar;Volume 90, 104998.

  Epigallocatechin-3-gallate + L-theanine/β-cyclodextrin inclusion complexes enhance epigallocatechin-3-gallate bioavailability and its lipid-lowering and weight loss effects
  Simvastatin (MK 733) purchased from AbMole

• 

  Molecules. 2022 Jul 31;27(15):4894.

  Metagenomics Approach to the Intestinal Microbiome Structure and Abundance in High-Fat-Diet-Induced Hyperlipidemic Rat Fed with (−)-Epigallocatechin-3-Gallate
  Simvastatin (MK 733) purchased from AbMole

• 

  Chem Res. 2021 Oct 18.

  Comprehensive Analysis of Differential Gene Expression Profile via RNA Sequencing in the Human Ovarian Cancer SKOV3 Cells Treated with Simvastatin
  Simvastatin (MK 733) purchased from AbMole

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  Pak J Pharm Sci. 2016 May;29(3 Suppl):1043-51.

  Chromatographic resolution of drug analogues: 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitors (statins)
  Simvastatin (MK 733) purchased from AbMole

Customer Product Validations & Biological Datas

	Source	Pak J Pharm Sci (2016). Figure 1. Simvastatin (Abmole Bioscience)
	Method	HPLC chromatogram
	Cell Lines
	Concentrations	200μg/ml
	Incubation Time
	Results	The results summarized in (table 1) obtained for pravastatin, rosuvastatin, pitavastatin, atorvastatin, fluvastatin, lovastatin and simvastatin were comparable with the corresponding labeled amounts.

Chemical Information

Molecular Weight	418.57
Formula	C25H38O5
CAS Number	79902-63-9
Solubility (25°C)	DMSO 80 mg/mL
Storage	Powder          -20°C   3 years ;  4°C   2 years In solvent       -80°C   6 months ;  -20°C   1 month

Conversion of different model animals based on BSA (PMID: 27057123)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

References

[1] Jaqueline Aparecida Duarte, et al. The potential use of simvastatin for cancer treatment: A review

[2] Tanzeela A Fattah, et al. Synthetic Approaches Towards Antihypercholesterolemic Drug Simvastatin

[3] Nawal M Al-Rasheed, et al. Simvastatin Ameliorates Diabetic Cardiomyopathy by Attenuating Oxidative Stress and Inflammation in Rats

[4] L B Ramsey, et al. The clinical pharmacogenetics implementation consortium guideline for SLCO1B1 and simvastatin-induced myopathy: 2014 update

[5] Weijiang Dong, et al. J Lipid Res . Differential effects of simvastatin and pravastatin on expression of Alzheimer's disease-related genes in human astrocytes and neuronal cells