HMG-CoA reductase (Ki = 0.2 nM); Simvastatin competitively inhibits HMG-CoA reductase with a K_i of 0.1–0.2 nM in cell-free assays [1]

Simvastatin is an inactive medication precursor that needs to be broken down into its hydroxy acid form in the liver in order to start working. It has no drug activity of its own. Sodium hydroxide (NaOH) can activate it in in vitro tests.
Activation of Simvastatin in vitro [13,14]
Method 1[13]: Simvastatin 5 mg can be activated by reconstituting in an ethanol/sodium hydroxide solution, incubated for 2 hours in a water bath preheated to 50°C. The drug was made to 1 mL with deionized water and pH adjusted to 7.
Method 2[14]: Simvastatin is an inactive lactone product and has to be converted to its active β-hydroxy acid form by solubilization in 0.1 N sodium hydroxide/ethanol at 50°C for 2 hours. The solution was neutralized with hydrochloride (0.1 M) at pH 7.2.

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Simvastatin has IC50 values of 19.3 nM, 13.3 nM, and 15.6 nM, respectively, which inhibit the synthesis of cholesterol in mouse LM cells, rat H4II E cells, and human Hep G2 cells[1]. Within 30 minutes, simvastatin increases serine 473 phosphorylation of Akt in a dose-dependent manner; peak phosphorylation happens at 1.0 µM[2]. Simvastatin (1.0 μM) suppresses serum-free media undergo apoptosis, speeds up the creation of vascular structures, and increases phosphorylation of the endogenous Akt substrate endothelial nitric oxide synthase (eNOS)[2]. Simvastatin has anti-inflammatory properties and decreases IFN-γ release at 10 μM, as well as the proliferation of PB-derived mononuclear cells and synovial fluorid cells from rheumatoid arthritis blood induced by anti-CD3/anti-CD28 antibodies[3]. Additionally, around 30% of cell-mediated macrophage TNF-γ release produced via cognate contacts is blocked by simvastatin (10 μM)[3]. In astrocytes and neuroblastoma cells, simvastatin (5 μM) dramatically decreases ABCA1 expression, apolipoprotein E expression in astrocytes, and enhances glycogen synthase kinase 3β and cyclin-dependent kinase 5 expression in SK-N-SH cells[7]. Exosome release can be inhibited by simvastatin[10]. Simvastatin slows tumor cell development and causes it to stop in the G0/G1 phase at 32 and 64 μM; 24, 48, and 72 hours[11]. In HepG2 and Huh7 cells, simvastatin (32 and 64 μM; 48 h) causes apoptosis[11].

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- HMG-CoA Reductase Inhibition:
1. Cell-Based Assays: Simvastatin inhibits cholesterol synthesis in mouse L-M fibroblasts (IC₅₀ = 19.3 nM), rat H4IIE hepatocytes (IC₅₀ = 13.3 nM), and human HepG2 cells (IC₅₀ = 15.6 nM) [1]
- Akt Activation:
1. Western Blot Analysis: Treatment of endothelial cells with simvastatin (1.0 μM) for 30 minutes induced dose-dependent phosphorylation of Akt at Ser473, enhancing phosphorylation of endothelial nitric oxide synthase (eNOS) [2]
- Inflammatory Modulation:
1. PBMC Proliferation Assay: Simvastatin (10 μM) reduced anti-CD3/CD28-stimulated proliferation of peripheral blood mononuclear cells (PBMCs) and synovial fluid cells from rheumatoid arthritis patients, suppressing IFN-γ release by ~30% [3]
2. Monocyte Migration Assay: Simvastatin (10 μM) decreased monocyte migration across human blood-brain barrier (BBB) endothelial cells by reducing secretion of chemokines CCL2 and CXCL10 [9]
- Alzheimer’s Disease-Related Gene Expression:
1. Human Astrocytes/Neuronal Cells: Simvastatin significantly reduced expression of ABCA1 (79% in astrocytes, 97% in neuroblastoma cells) and apolipoprotein E (ApoE) while increasing tau protein expression in neuronal cells [7]

When administered po, simvastatin inhibits the conversion of radiolabeled acetate to cholesterol with an IC50 of 0.2 mg/kg[1]. In rabbits fed an atherogenci cholesterol-rich diet, simvastatin (4 mg/day, po for 13 weeks) reverses the increases in total cholesterol, LDL cholesterol, and HDL cholesterol to normal levels[4]. In rabbits fed a diet containing 0.25% cholesterol, simvastatin (6 mg/kg) increases the number of hepatic LDL receptors and LDL receptor-dependent binding[5]. In cynomolgus monkeys fed an atherogenic diet, simvastatin (20 mg/kg/day) causes a 1.3-fold decrease in macrophage content in lesions and a 2-fold decrease in vascular cell adhesion molecule-1, interleukin-1beta, and tissue factor expression. These reductions are accompanied by a 2.1-fold increase in lesional smooth muscle cell and collagen content[6]. Treatment with simvastatin (oral gavage; once daily; 14 d); 15 and 30 mg/kg) reduces oxidative damage, TNF-a and IL-6 levels, and revives the activities of the mitochondrial enzyme complex[12].

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- Hypercholesterolemia in Rabbits:
1. Cholesterol-Feeding Model: Oral administration of simvastatin (4 mg/day for 13 weeks) normalized serum total cholesterol, LDL-C, and HDL-C levels in cholesterol-fed rabbits, reducing atherosclerotic lesion formation [4]
2. LDL Receptor Upregulation: Simvastatin (6 mg/kg) increased hepatic LDL receptor binding and expression in rabbits, enhancing LDL clearance [5]
- Inflammatory Arthritis:
1. Collagen-Induced Arthritis Model: Simvastatin (10 mg/kg/day, orally) reduced joint swelling and histological inflammation in rats, decreasing pro-inflammatory cytokines (TNF-α, IL-1β) [3]
- Liver Ischemia-Reperfusion Injury:
1. Rat Model: Pretreatment with simvastatin (20 mg/kg, intraperitoneal) before warm ischemia preserved hepatic ATP levels, reduced ALT/AST release, and attenuated oxidative stress via KLF2-dependent upregulation of eNOS, thrombomodulin (TM), and heme oxygenase-1 (HO-1) [8]
- Blood-Brain Barrier Permeability:
1. Human BBB Model: Simvastatin (9.5×10^-8 M) reduced bovine serum albumin and [¹⁴C]-sucrose diffusion across human BBB endothelial cells in vitro, restricting leukocyte migration [9]

- HMG-CoA Reductase Activity Assay [1]:
1. Reaction Setup: Recombinant HMG-CoA reductase (10 nM) was incubated with simvastatin (0.1–10 μM) and radiolabeled [³H]-HMG-CoA (100 μM) in buffer (50 mM Tris-HCl, pH 7.5, 10 mM MgCl₂, 1 mM DTT).
2. Product Detection: Conversion of [³H]-HMG-CoA to mevalonate was measured by liquid scintillation counting, yielding a K_i of 0.1–0.2 nM for simvastatin [1]
For assessment of Akt protein kinase activity in vitro, substrate (2 μg histone H2B or 25 μg eNOS peptide) is incubated with Akt immunoprecipitated from cell lysate using goat polyclonal anti-Akt1 antibody. Kinase reactions are initiated following the addition of Simvastatin to a final concentration of ATP (50 μM) containing 10 μCi of 32P-γATP, dithiotreitol (1 mM), HEPES buffer (20 mM, pH 7.4), MnCl2 (10 mM), MgCl2 (10 mM). After incubation for 30 min at 30°C, phosphorylated histone H2B is visualized after SDS-PAGE (15%) and autoradiography. To estimate the extent of 32P incorporation into eNOS peptides, each reaction mixture is measured by spotting onto phosphocellulose disc filter and the amount of phosphate incorporated is measured by Cerenkov counting. The wild-type peptide sequence is 1174-RIRTQSFSLQERHLRGAVPWA-1194, and the mutant eNOS peptide is identical except that serine 1179 is substituted by alanine[3].

Cell Proliferation Assay[11]
Cell Types: HepG2 and Huh7 cells
Tested Concentrations: 32 and 64 μM
Incubation Duration: 24, 48, and 72 hrs (hours)
Experimental Results: Inhibited tumor cell growth as compared to controls (ctrl, p<0.05).

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Apoptosis Analysis[11]
Cell Types: HepG2 and Huh7 cells
Tested Concentrations: 32 and 64 μM
Incubation Duration: 48 hrs (hours)
Experimental Results: Increased early apoptosis from 9.2% in non-treated ctrl cells to 18.2% (32 μM) and 19.8% (64 μM), respectively, increased late apoptosis from 35.0% in ctrl cells to 56.9% (32 μM) and 48.0% (64 μM), respectively, in HepG2 cells.

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Cell Cycle Analysis[11]
Cell Types: HepG2 and Huh7 cells
Tested Concentrations: 32 and 64 μM
Incubation Duration: 24, 48, and 72 hrs (hours)
Experimental Results: demonstrated downregulation of CDK1, CDK2, CDK4 and cyclins D1 and E as compared to ctrl tumor cells.

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- Akt Phosphorylation Assay [2]:
1. Cell Culture: Human umbilical vein endothelial cells (HUVECs) were serum-starved overnight and treated with simvastatin (0.1–10 μM) for 30 minutes.
2. Western Blot: Phosphorylated Akt (p-Akt) and total Akt were detected using specific antibodies, showing maximal p-Akt at 1.0 μM [2]
- Blood-Brain Barrier Permeability Assay [9]:
1. Transwell System: Human BBB endothelial cells were grown on transwell inserts and treated with simvastatin (10 μM). Permeability to 70 kDa FITC-dextran was measured fluorometrically, revealing a 50–60% reduction [9]

Animal/Disease Models: Male wistar rats with oxidative damage by Intrastriatal 6-OHDA administration[12]
Doses: 15 and 30 mg/kg
Route of Administration: po (oral gavage); 15 and 30 mg/kg; one time/day; 14 days
Experimental Results: Attenuated oxidative damage (decreased MDA, nitrite levels and restoration of decreased GSH), attenuated TNF-a and IL-6 levels, and restored itochondrial enzyme complex activities as compared to 6-OHDA group.

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- Rabbit Hypercholesterolemia Model [4]:
1. Diet and Treatment: Rabbits were fed a 1% cholesterol diet for 13 weeks. Simvastatin (4 mg/day) was administered orally via gastric gavage.
2. Sample Collection: Serum lipids were measured at baseline and weekly intervals; aortic lesions were analyzed histologically [4]
- Rat Liver Ischemia-Reperfusion Model [8]:
1. Pretreatment: Rats received simvastatin (20 mg/kg, i.p.) 30 minutes before 30 minutes of hepatic ischemia.
2. Reperfusion: Livers were cold-stored in UW solution for 24 hours, then reperfused ex vivo for 60 minutes. Hepatic ATP, ALT/AST, and oxidative stress markers were assessed [8]

Absorption, Distribution and Excretion
Peak plasma concentrations of both the active inhibitor and the total inhibitor were reached within 1.3 to 2.4 hours after administration. Although the recommended therapeutic dose range is 10 to 40 mg/day, the linear relationship of AUC did not deviate significantly even when the dose was increased to 120 mg. Immediate administration of simvastatin before a meal did not affect the plasma concentration profile of the inhibitor compared to fasting. In a pharmacokinetic study involving 17 healthy Chinese volunteers, the main pharmacokinetic parameters were as follows: Tmax 1.44 h, Cmax 9.83 μg/L, t1/2 4.85 h, and AUC 40.32 μg·h/L. Simvastatin experiences a broad first-pass effect in the liver (the target organ and primary site of action for HMG-CoA reductase inhibitors). The tissue selectivity of orally administered simvastatin (and consequently, the lower systemic exposure) is significantly higher than that of administration in its enzymatic active form (i.e., the open hydroxy acid). Animal studies have shown that simvastatin concentrations in the liver are significantly higher than in non-target tissues after oral administration. However, due to extensive first-pass metabolism, simvastatin has low systemic bioavailability. A single-dose study in nine healthy subjects estimated that less than 5% of the oral dose of simvastatin enters systemic circulation as an active inhibitor. Genetic differences in the hepatic transporter OATP1B1 (organic anion transport polypeptide 1B1), encoded by the SCLCO1B1 gene (a member of the solute carrier organic anion transporter family 1B1), have been shown to affect the pharmacokinetics of simvastatin. Pharmacogenetic studies have shown that the c.521T>C single nucleotide polymorphism (SNP) resulted in a mean 3.2-fold increase in plasma simvastatin concentrations compared to 521TT homozygous individuals. The 521CC genotype was also associated with a significantly increased risk of myopathy, likely due to increased systemic exposure. Other statins affected by this polymorphism include rosuvastatin, pitavastatin, atorvastatin, lovastatin, and pravastatin. For patients known to carry the c.521CC OATP1B1 genotype, a maximum daily dose of simvastatin is recommended to avoid the risk of adverse reactions due to increased drug exposure, such as muscle pain and rhabdomyolysis. Other statins, such as rosuvastatin, have also been shown to increase plasma concentrations of these statins when used concomitantly with breast cancer resistance protein (BCRP) inhibitors (e.g., elbasvir and grazoprevir). However, further evidence is needed, and dose adjustments for simvastatin may be necessary. Other statins affected by this polymorphism include fluvastatin and atorvastatin. Following oral administration of 14C-labeled simvastatin in humans, 13% of the dose is excreted in the urine and 60% in the feces.
Rat studies have shown that when radiolabeled simvastatin is administered, simvastatin-derived radioactive substances can cross the blood-brain barrier.
Simvastatin and its β-hydroxy acid metabolites are highly bound to human plasma proteins (approximately 95%). Rat studies have shown that when radiolabeled simvastatin is administered, simvastatin-derived radioactive substances can cross the blood-brain barrier.
/Breast Milk/ It is currently unclear whether simvastatin is distributed in human breast milk…
After oral administration of 14C-labeled simvastatin in humans, 13% of the dose is excreted in the urine and 60% in the feces. The concentration of total radioactive substances in plasma (simvastatin plus 14C metabolites) peaks at 4 hours post-administration and declines rapidly, reaching approximately 10% of the peak value by 12 hours post-administration. Due to extensive first-pass metabolism in the liver, the bioavailability of simvastatin in systemic circulation is low (<5%).
This study investigated the absorption, distribution, and excretion of 14C-simvastatin in male rats after 21 consecutive days of oral administration at a dose of 10 mg/kg. One hour after each administration, the plasma concentration of 14C-simvastatin did not increase during the administration period or after repeated administration. The radioactivity level-time curve after the last administration was similar to that after the first administration. Within 96 hours after the last administration, the cumulative excretion of radioactive material in urine and feces accounted for 9.0% and 91.4% of the total dose, respectively. After the last administration, the radioactive material was mainly concentrated in the gastrointestinal tract, liver, and kidneys. Its distribution pattern was similar to that after a single administration. No accumulation of the drug or its metabolites was observed in rat tissues after continuous oral administration of (14)C-simvastatin. In pregnant and lactating rats, placental transport and milk excretion of radioactive material were investigated after a single oral administration of (14)C-simvastatin. Whole-body autoradiography of rats on days 12 and 18 of gestation showed that the radioactive material was distributed minimally in the fetus and was rapidly cleared. On day 18 of gestation, the radioactivity concentrations in the placenta, amniotic fluid, and fetal tissues were almost equal to or lower than those in maternal plasma. The amount of radioactivity transferred to the fetus was approximately 0.02% of the oral dose. The concentration of radioactive material in breast milk was approximately 20-54% of the concentration in maternal plasma.
For more complete data on absorption, distribution, and excretion of simvastatin (6 items), please visit the HSDB record page.

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Metabolism/Metabolites
Simvastatin is administered as an inactive lactone derivative and then metabolized to a β-hydroxy acid form via spontaneous chemical conversion and nonspecific carboxylesterase-mediated enzymatic hydrolysis in the intestinal wall, liver, and plasma. Oxidative metabolism in the liver is primarily mediated by CYP3A4 and CYP3A5, with the remaining metabolism occurring via CYP2C8 and CYP2C9. The major active metabolites of simvastatin are β-hydroxy acid metabolites and their 6'-hydroxy, 6'-hydroxymethyl, and 6'-methylene derivatives. Polymorphisms in the CYP3A5 gene have been shown to affect the in vivo distribution of simvastatin and may provide a plausible explanation for individual variability in its distribution and pharmacokinetics. The major active metabolites of simvastatin in human plasma are simvastatin β-hydroxy acid and its 6'-hydroxy, 6'-hydroxymethyl, and 6'-methylene derivatives. Known human metabolites of simvastatin include 6'-α-hydroxysimvastatin, 6'-methylene, and 3',5'-dihydrodiol. In the liver, simvastatin is a substrate of CYP3A4. The major active metabolites of simvastatin are 6'-hydroxy acid metabolites and their 6'-hydroxy, 6'-hydroxymethyl, and 6'-methylene derivatives.
Elimination pathway: After oral administration of 14C-labeled simvastatin in humans, 13% of the dose is excreted in urine and 60% in feces.
Half-life: 3 hours

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Biological half-life
4.85 hours

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Absorption:
1. Oral bioavailability: Simvastatin has low oral bioavailability (approximately 5%), which is due to its extensive first-pass hepatic metabolism[1].
- Metabolism:
1. Cytochrome P450: mainly metabolized by CYP3A4 into active metabolites (e.g., simvastatin acid), which contribute to HMG-CoA reductase inhibition [5]
- Half-life:
1. Plasma half-life: approximately 2 hours for the parent compound; approximately 19 hours for the active metabolites [1]
- Excretion:
1. Bile excretion: approximately 60% of the dose is excreted in feces; approximately 13% is excreted in urine [1]

Toxicity Summary
Identification and Uses: Simvastatin is a cholesterol-lowering drug and an inhibitor of hydroxymethylglutaryl-CoA reductase. Human Exposure and Toxicity: Simvastatin can occasionally cause myopathy, manifested as muscle pain, tenderness, or weakness, with creatine kinase levels exceeding ten times the upper limit of normal. Myopathy sometimes presents as rhabdomyolysis, with or without myoglobinuria leading to acute renal failure, and rare fatalities. High plasma statin activity levels increase the risk of myopathy. Predisposing factors for myopathy include advanced age (≥65 years), female sex, uncontrolled hypothyroidism, and renal impairment. Although myopathy (including rhabdomyolysis) is a known adverse reaction to all statins, studies have shown that patients taking higher doses of simvastatin may have a higher risk of muscle damage than those taking lower doses, or possibly other statins. Animal Studies: A single oral dose of 9 g/m² resulted in significant lethality in mice. No lethality was observed in rats and dogs treated with 30 g/m² and 100 g/m² doses, respectively. No specific diagnostic signs were observed in rodents. At these doses, dogs only experienced vomiting and mucus in their stool. Clinically normal dogs developed optic nerve degeneration after 14 weeks of simvastatin treatment (at a dose of 180 mg/kg/day), with mean plasma drug concentrations at this dose approximately 12 times higher than those in humans at 80 mg/day. Female rats developed cataracts two years after treatment with 50 mg/kg/day and 100 mg/kg/day, respectively, while dogs developed cataracts three months after treatment with 90 mg/kg/day and two years after treatment with 50 mg/kg/day, respectively. The incidence of thyroid follicular adenomas increased in female rats after 2 years of simvastatin treatment. After 72 weeks of daily treatment with simvastatin at doses of 25, 100, and 400 mg/kg, respectively, the incidence of hepatocellular carcinoma increased in female mice receiving 400 mg/kg daily and in male mice receiving 100 and 400 mg/kg daily. The incidence of hepatocellular carcinoma was highest in male mice, reaching 90%. The incidence of hepatic adenomas also increased in female mice receiving 100 and 400 mg/kg daily. Regardless of sex, the incidence of lung adenomas increased in mice receiving 100 and 400 mg/kg daily; the incidence of Haver's gland (ocular gland in rodents) adenomas also increased in mice receiving 400 mg/kg daily. No tumorigenesis was observed in mice receiving 25 mg/kg daily in this study. Central nervous system vascular lesions, characterized by perivascular hemorrhage and edema, perivascular interstitial mononuclear cell infiltration, perivascular fibrin deposition, and small vessel necrosis, were observed in dogs receiving simvastatin at a dose of 360 mg/kg/day. Decreased fertility was observed in male rats treated with simvastatin 25 mg/kg/day for 34 weeks. This effect was not observed in a subsequent study using the same dose for 11 weeks (covering the entire spermatogenesis cycle in rats, including epididymal maturation). No microscopic changes in the testes were observed in either study. In rats, seminiferous tubule degeneration was observed when simvastatin was administered at a dose of 180 mg/kg/day. Simvastatin did not exhibit mutagenicity in in vitro microbial mutagenesis (Ames) assays using Salmonella typhimurium mutants, either activated or unactivated by rat or mouse liver metabolism; in alkaline elution assays using rat hepatocytes; in V-79 mammalian cell positive mutation studies; in hamster ovary cell chromosomal aberration studies; and in vivo mouse bone marrow chromosomal aberration assays. Simvastatin is a prodrug whose six-membered lactone ring is hydrolyzed in vivo to form a β,δ-dihydroxy acid, an active metabolite structurally similar to HMG-CoA (hydroxymethylglutaryl-CoA). After hydrolysis, simvastatin competes with HMG-CoA for HMG-CoA reductase (a liver microsomal enzyme). Interfering with the activity of this enzyme reduces the levels of mevalonate (a precursor to cholesterol).
Hepatotoxicity
In patients taking simvastatin long-term, up to 5% may experience a mild elevation in serum ALT levels during treatment, but only 1% to 2% will have a confirmed ALT level more than three times the upper limit of normal (ULN). These abnormalities are usually asymptomatic and resolve spontaneously even with continued treatment. ALT elevations are more common in patients taking higher doses of simvastatin (40 and 80 mg daily). In several studies, the incidence of ALT elevation was not higher in patients taking 10 and 20 mg of simvastatin daily than in the placebo group. Clinically significant liver damage caused by simvastatin is rare. The incubation period for liver disease symptoms is typically 1 week to 3 years, but in most cases, the incubation period is 1 to 6 months. The injury pattern is diverse, with reported types including hepatocellular, cholestatic, or mixed. Immune hypersensitivity symptoms such as fever and rash are uncommon. Cases of autoimmune hepatitis-like syndromes associated with simvastatin treatment have been reported, some of which did not fully reverse upon discontinuation of the drug, eventually developing into chronic hepatitis requiring long-term immunosuppressive therapy. However, most cases recover within 1 to 3 months. Rare cases of acute liver failure and death have also been associated with simvastatin. However, given the widespread use of simvastatin, clinically significant liver injury is extremely rare, estimated at 1 case per 100,000 patient-years of exposure.
Probability Score: A (Well-known but rare cause of clinically significant liver injury).
Pregnancy and Lactation Effects
◉ Overview of Use During Lactation
Currently, there is no published information regarding the use of simvastatin during lactation. Due to concerns about disrupting lipid metabolism in infants, the consensus is that simvastatin should not be used during lactation. However, some argue that children with homozygous familial hypercholesterolemia who start statin therapy at age 1 have low oral bioavailability and pose a lower risk to breastfed infants, especially rosuvastatin and pravastatin. [1] Until more data are available, especially during the breastfeeding neonatal or preterm period, other medications may be preferred.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding
Simvastatin and its β-hydroxy acid metabolites are highly bound to human plasma proteins (approximately 95%).

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Drug interactions
Statins are widely used to treat patients with hyperlipidemia after organ transplantation. We report a case of a heart transplant patient who developed severe rhabdomyolysis and acute renal failure after switching from pravastatin to simvastatin. Other medications this patient was taking concurrently included cyclosporine A and diltiazem. Unlike pravastatin, the metabolism and tissue concentrations of simvastatin (and other statins) are significantly affected by these drugs. ...
Potential CYP3A4 inhibitor: Simvastatin, like several other HMG-CoA reductase inhibitors, is a substrate of CYP3A4. Simvastatin is metabolized by CYP3A4 but does not itself possess CYP3A4 inhibitory activity; therefore, it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. Elevated plasma HMG-CoA reductase inhibitory activity increases the risk of myopathy and rhabdomyolysis, especially when taking higher doses of simvastatin. Concomitant use of drugs labeled as having potent CYP3A4 inhibitory activity is contraindicated. If treatment with itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, or telithromycin is necessary, simvastatin treatment must be discontinued during treatment. In one study, concomitant use of digoxin and simvastatin resulted in a slight increase in plasma digoxin concentrations. Patients taking digoxin should be appropriately monitored when starting simvastatin. Concomitant use of amiodarone, dronedarone, ranolazine, or calcium channel blockers (such as verapamil, diltiazem, or amlodipine) increases the risk of myopathy, including rhabdomyolysis. For more complete data on drug interactions with simvastatin (19 in total), please visit the HSDB record page.

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Non-human toxicity values
LD50 rat (female) subcutaneous injection 672 mg/kg
LD50 rat (male) subcutaneous injection 1088 mg/kg
LD50 rat (male) intraperitoneal injection 898 mg/kg
LD50 rat (female) intraperitoneal injection 705 mg/kg
For more complete data on non-human toxicity values of simvastatin (out of 13), please visit the HSDB record page.

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- Hepatotoxicity:
1. Rat studies: Long-term use of simvastatin (20–40 mg/kg/day for 30 days) increased serum ALT/AST levels and hepatic lipid peroxidation, which could be reversed by combination with naringin[7]
- Myopathy risk:
1. Drug interactions: Combination with CYP3A4 inhibitors (e.g. cyclosporine) increased plasma simvastatin levels and increased the risk of rhabdomyolysis[5]
- Carcinogenicity:
1. Mouse studies: High doses of simvastatin (400 mg/kg/day) increased the incidence of hepatic adenoma/carcinoma in mice, possibly due to peroxisome proliferator-activated receptor (PPAR) activation[1]

[1]. Mechanism of action and biological profile of HMG CoA reductase inhibitors. A new therapeutic alternative. Drugs, 1988. 36 Suppl 3: p. 72-82.

[2]. 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.

[3]. A novel anti-inflammatory role for simvastatin in inflammatory arthritis. J Immunol. 2003 Feb 1;170(3):1524-30.

[4]. 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.

[5]. 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.

[6]. 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.

[7]. 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]. 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.

[9]. Statins reduce human blood-brain barrier permeability and restrict leukocyte migration: relevance to multiple sclerosis. Ann Neurol. 2006 Jul;60(1):45-55.

[10]. Advances in the discovery of exosome inhibitors in cancer. J Enzyme Inhib Med Chem. 2020;35(1):1322-1330.

Therapeutic Uses

Cholesterol-lowering drugs; HMG-CoA reductase inhibitors
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that indexes human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes a summary of the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure under investigation); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (for providing patient health information) and PubMed (for providing citations and abstracts of academic articles in the medical field). Simvastatin is indexed in the database. Zocor is indicated for adolescents aged 10-17 years with heterozygous familial hypercholesterolemia (HeFH) at least one year after menarche, as adjunctive therapy to lower total cholesterol (TCC), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (Apo B) levels. This is contingent on the patient having, after adequately trying dietary therapy, an LDL-C ≥ 190 mg/dL; or an LDL-C ≥ 160 mg/dL with a family history of early-onset cardiovascular disease (CVD), or the presence of two or more other CVD risk factors. The minimum treatment goal for children and adolescents is to achieve a mean LDL-C < 130 mg/dL. The optimal age to begin lipid-lowering therapy to reduce the risk of developing symptomatic coronary artery disease (CAD) in adulthood has not yet been determined. /US Product Label Includes/
Zocor is indicated for: lowering total cholesterol (total cholesterol), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and triglycerides (TG) in patients with primary hyperlipidemia (Fredrickson type IIa, heterozygous familial and non-familial) or mixed dyslipidemia (Fredrickson type IIb), and raising high-density lipoprotein cholesterol (HDL-C); lowering triglycerides (TG) in patients with hypertriglyceridemia (Fredrickson type IV); and lowering triglycerides (TG) and very low-density lipoprotein cholesterol (VLDL-C) in patients with primary β-lipoprotein dyslipidemia (Fredrickson type III). For patients with homozygous familial hypercholesterolemia (HoFH), it can lower total cholesterol (Total-C) and low-density lipoprotein cholesterol (LDL-C) levels as adjunctive therapy to other lipid-lowering treatments (e.g., LDL plasma exchange), or when such treatments are not feasible.
For more complete data on the therapeutic uses of simvastatin (11 in total), please visit the HSDB records page.

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Drug Warnings
Zocor is contraindicated in pregnant women or women who may become pregnant. Lipid-lowering drugs are ineffective during pregnancy because cholesterol and its derivatives are essential for normal fetal development. Atherosclerosis is a chronic process, and discontinuing lipid-lowering drugs during pregnancy has little effect on the long-term efficacy of treatment for primary hypercholesterolemia. …Serious cholesterol and triglyceride levels are elevated during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because statins reduce cholesterol synthesis and may reduce the synthesis of other cholesterol-derived bioactive substances, taking Zocor (Zocor) during pregnancy may harm the fetus. If Zocor is taken during pregnancy, or if a patient becomes pregnant while taking this medication, the patient should be informed of the potential harm to the fetus.
Grapefruit juice contains one or more components that inhibit CYP3A4, which can increase the plasma concentration of drugs metabolized by CYP3A4. The effect of the usual amount consumed (one 250 ml cup daily) is minimal (13% increase in active plasma HMG-CoA reductase inhibitory activity as determined by the area under the concentration-time curve) and has no clinical significance. However, because larger doses of grapefruit juice can significantly increase plasma HMG-CoA reductase inhibitory activity, grapefruit juice should be avoided while taking simvastatin. It is currently unknown whether simvastatin is excreted into human breast milk. Because small amounts of components of this class of drugs are excreted into breast milk and can cause serious adverse reactions in breastfeeding infants, women taking simvastatin should not breastfeed. The importance of the medication to the mother should be weighed when deciding whether to discontinue breastfeeding or discontinue the medication. Because advanced age (≥65 years) is a predisposing factor for myopathy (including rhabdomyolysis), caution should be exercised when older adults take Zocor. In a clinical trial of simvastatin 80 mg/day, patients ≥65 years of age had an increased risk of developing myopathy (including rhabdomyolysis) compared to patients under 65 years of age. For more complete data on simvastatin warnings (33 in total), please visit the HSDB records page.

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Pharmacodynamics
Simvastatin is an oral lipid-lowering drug that inhibits HMG-CoA reductase. It is used to lower plasma concentrations of total cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apoB), non-high-density lipoprotein cholesterol (non-HDL-C), and triglycerides (TG), while increasing plasma concentrations of high-density lipoprotein cholesterol (HDL-C). High LDL-C, low HDL-C, and high TG concentrations in plasma are associated with an increased risk of atherosclerosis and cardiovascular disease. The ratio of total cholesterol to high-density lipoprotein cholesterol (HDL-C) is a strong predictor of coronary artery disease, and a high ratio is associated with a higher risk of disease. Elevated HDL-C levels are associated with a reduced cardiovascular risk. Rosuvastatin reduces the incidence and mortality of cardiovascular disease by lowering low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels and raising HDL-C levels. Elevated cholesterol levels, especially LDL levels, are a significant risk factor for cardiovascular disease (CVD). Multiple landmark studies have demonstrated that using statins to lower LDL levels significantly reduces the risk of CVD and all-cause mortality. Because statins can reduce all-cause mortality, including fatal and non-fatal CVD, and decrease the need for revascularization or angioplasty after a heart attack, they are considered a cost-effective CVD treatment option. Evidence suggests that even in low-risk individuals (with a 5-year risk of a major vascular event <10%), statins can reduce the relative risk of major cardiovascular events (heart attack, stroke, coronary revascularization, and death from coronary artery disease) by 20%–22% for every 1 mmol/L reduction in LDL-C, without significant side effects or risks. Skeletal Muscle Effects Simvastatin can occasionally cause myopathy, manifested as muscle pain, tenderness, or weakness, with creatine kinase (CK) levels exceeding 10 times the upper limit of normal (ULN). Myopathy sometimes presents as rhabdomyolysis, with or without myoglobinuria leading to acute renal failure, and in rare cases, death. Predisposing factors for myopathy include advanced age (≥65 years), female sex, uncontrolled hypothyroidism, and renal impairment. The risk of myopathy may also be increased in Chinese patients. In most cases, muscle symptoms and elevated CK levels resolve upon timely discontinuation of the drug. In a clinical trial database of 41,413 patients, the incidence of myopathy was approximately 0.03% and 0.08% with daily doses of 20 mg and 40 mg simvastatin, respectively. The risk of myopathy was significantly higher with daily doses of 80 mg simvastatin (0.61%) than in the lower dose group. Therefore, it is recommended that the 80 mg dose of simvastatin be used only in patients who have been taking 80 mg simvastatin for a long period (e.g., 12 months or longer) and have no evidence of muscle toxicity. Furthermore, patients who are already taking 80 mg simvastatin should be closely monitored for evidence of muscle toxicity; if it is necessary to start medications that interact with simvastatin in a way that is contraindicated or has a maximum dose limit, the patient should be switched to another statin with a lower likelihood of drug interaction. The risk of myopathy may increase if simvastatin is taken concurrently with interacting medications such as fenofibrate, niacin, gemfibrozil, cyclosporine, or potent CYP3A4 enzyme inhibitors. There have been reports of HMG-CoA reductase inhibitors causing myopathy, including rhabdomyolysis, when used in combination with colchicine; therefore, caution should be exercised when taking these two medications concurrently. Liver Enzyme Abnormalities In clinical studies, approximately 1% of patients receiving simvastatin treatment experienced persistently elevated serum transaminase levels (more than 3 times the upper limit of normal). When these patients discontinue or stop treatment, transaminase levels typically slowly decrease to pre-treatment levels. Elevated transaminase levels were not associated with jaundice or other clinical signs or symptoms. In the Scandinavian Simvastatin Survival Study (4S), there was no significant difference in the number of patients with transaminase elevations exceeding three times the upper limit of normal during the study period between the simvastatin and placebo groups (14 patients [0.7%] vs. 12 patients [0.6%]). In the first year of the study, the incidence of a single alanine aminotransferase (ALT) elevation to three times the upper limit of normal was significantly higher in the simvastatin group than in the placebo group (20 patients vs. 8 patients, p=0.023), but thereafter there was no significant difference between the two groups. In the Cardiac Protection Study (HPS), 20,536 patients were randomized to receive simvastatin 40 mg/day or placebo. The incidence of elevated transaminases (confirmed by retesting to be more than 3 times the upper limit of normal) was 0.21% (n=21) in the simvastatin group and 0.09% (n=9) in the placebo group. Endocrine Effects HMG-CoA reductase inhibitors (including simvastatin) have been reported to cause elevated glycated hemoglobin (HbA1c) and fasting blood glucose levels. Although cholesterol is a precursor to all steroid hormones, studies with simvastatin have shown that the drug has no clinical effect on steroid production. Simvastatin does not increase gallstone formation and is therefore not expected to increase the incidence of gallstones.

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- Mechanism of action:
1. Dual action:simvastatin inhibits cholesterol biosynthesis through HMG-CoA reductase and promotes angiogenesis/vasodilation through Akt/eNOS activation[2]
2. KLF2-dependent protection: In hepatic ischemia-reperfusion injury,simvastatin upregulates KLF2, thereby transcribedly activating anti-inflammatory and cytoprotective genes (e.g., eNOS, HO-1)[8]
- Indications:
1. Primary use: Treatment of hypercholesterolemia to reduce LDL-C and cardiovascular risk[1]
2. Off-label use: Neuroprotection after stroke, anti-inflammatory treatment of rheumatoid arthritis, and reduction of blood-brain barrier permeability in patients with multiple sclerosis[3,9]
- FDA warning:
1. Muscle toxicity: There is a risk of myopathy/rhabdomyolysis, especially at high doses or when used in combination with CYP3A4 inhibitors [1]

C25H38O5

418.57

418.271

C, 71.74; H, 9.15; O, 19.11

79902-63-9

Simvastatin-d6;1002347-71-8;Simvastatin-d11;1002347-74-1;Simvastatin-d3;1002347-61-6; 139893-43-9 (ammonium); 79902-63-9 (free); 101314-97-0 (sodium)

54454

White to off-white crystalline powder from n-butyl chloride + hexane

1.1±0.1 g/cm3

564.9±50.0 °C at 760 mmHg

139 °C

184.8±23.6 °C

0.0±3.5 mmHg at 25°C

1.530

4.41

1

5

7

30

706

7

O([C@H]1C[C@@H](C)C=C2C=C[C@@H]([C@@H]([C@@H]12)CC[C@H]1OC(=O)C[C@H](O)C1)C)C(=O)C(C)(C)CC

RYMZZMVNJRMUDD-OVOOIQHOSA-N

InChI=1S/C25H38O5/c1-6-25(4,5)24(28)30-21-12-15(2)11-17-8-7-16(3)20(23(17)21)10-9-19-13-18(26)14-22(27)29-19/h7-8,11,15-16,18-21,23,26H,6,9-10,12-14H2,1-5H3/t15-,16-,18+,19+,20-,21-,23?/m0/s1

(1S,3R,7S,8S)-8-(2-((2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2,2-dimethylbutanoate

MK-0733, MK 0733, MK0733, Zocor; Synvinolin; MK 733; Sinvacor; MK-733; MK733; Simvastatin; Denan; Lipex;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.97 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.5 mg/mL (5.97 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.97 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: ≥ 2.5 mg/mL (5.97 mM) (saturation unknown) in 10% EtOH + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix well.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 5: ≥ 2.5 mg/mL (5.97 mM) (saturation unknown) in 10% EtOH + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 6: 2% DMSO+30% PEG 300+5% Tween80+ddH2O:10 mg/mL

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Solubility in Formulation 7: 10 mg/mL (23.89 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)