Fluvastatin is a competitive inhibitor of HMG-CoA reductase (HMGCR), the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, the rate-limiting step in cholesterol synthesis. By inhibiting this enzyme, Fluvastatin reduces de novo cholesterol biosynthesis in the liver, leading to increased clearance of low-density lipoprotein (LDL) cholesterol from the blood. It also exhibits antineoplastic properties and has been shown to inhibit cell proliferation, induce apoptosis, and protect against oxidative stress. In human hepatocellular carcinoma cells, Fluvastatin induces G2/M phase arrest.

The enzyme hydroxymethylglutaryl-CoA reductase (HMGCR), which catalyzes the conversion of HMG-CoA to mevalonate, the rate-limiting enzyme in cholesterol production, is competitively inhibited by fluvastatin (XU 62-320 free acid). move. Research on human HCC cells has demonstrated that fluvastatin causes G2/M phase arrest. HCC cells expressed more cytochrome c, Bax, cleaved caspase-3, and reduced expression of Bcl-2 and procaspase-9 when fluvastatin (XU 62320) was present. Because of its antilipidemic properties, fluvastatin (XU 62320) is prescribed to lower plasma cholesterol and prevent cardiovascular disease.
In vitro, Fluvastatin is a potent and competitive inhibitor of HMGCR. It inhibits cell proliferation, induces apoptosis, and protects against oxidative stress. In human hepatocellular carcinoma cell (HCC) studies, Fluvastatin induces G2/M phase arrest. The compound also exhibits antineoplastic properties. Its in vitro activity is characterized by its ability to inhibit cholesterol synthesis and modulate cell cycle progression. Fluvastatin's effects on cell proliferation and apoptosis are mediated through its inhibition of the mevalonate pathway, which is essential for cell growth and survival.

In vivo, Fluvastatin is used as an adjunct to dietary therapy to prevent cardiovascular events. It is used as secondary prevention in patients with coronary heart disease (CHD). The compound reduces plasma cholesterol levels and prevents cardiovascular disease. Fluvastatin's in vivo efficacy is attributed to its ability to inhibit HMG-CoA reductase in the liver, leading to reduced cholesterol synthesis and increased LDL clearance. Its antineoplastic properties have also been investigated in preclinical models. The compound is orally active and has a favorable pharmacokinetic profile.

In vitro enzyme assays for Fluvastatin typically involve measuring the inhibition of HMG-CoA reductase (HMGCR) activity. The enzyme catalyzes the conversion of HMG-CoA to mevalonate, and the inhibition is quantified by determining the IC50. Fluvastatin is a competitive inhibitor of HMGCR. These assays confirm the mechanism of action as a statin. The compound's ability to inhibit cholesterol synthesis can also be assessed using cell-based assays measuring cholesterol incorporation or mevalonate production. Fluvastatin's affinity for HMGCR is well-characterized.

In vitro cellular assays for Fluvastatin typically involve treating cancer cell lines with the compound and measuring cell viability, proliferation, and apoptosis. In human hepatocellular carcinoma cells, Fluvastatin induces G2/M phase arrest. The compound inhibits cell proliferation and induces apoptosis in various cancer cell lines. These cell-based assays demonstrate the compound's antiproliferative effects, which are mediated through the inhibition of the mevalonate pathway. Fluvastatin also protects against oxidative stress in cellular models.

In vivo animal models for Fluvastatin typically involve hypercholesterolemic animal models to evaluate its lipid-lowering efficacy. The compound is administered orally, and plasma cholesterol levels are measured. Fluvastatin has also been studied in cancer models to assess its antineoplastic properties. In these models, tumor growth inhibition is measured. The compound's oral bioavailability supports its use in these in vivo studies. Doses and administration routes are optimized based on the specific model and experimental endpoints. These studies provide evidence for the compound's in vivo efficacy.

Absorption, Distribution and Excretion
Absorption is rapid and almost complete (>90%), but first-pass metabolism is extensive. At a 10 mg dose, bioavailability is 24% (range 9-50%). Compared to immediate-release capsules taken on an empty stomach, the mean relative bioavailability of extended-release tablets is 29% (range: 9% to 66%). After oral administration, fluvastatin reaches peak plasma concentration (Tmax) in less than 1 hour. Taking extended-release tablets with a high-fat diet delays absorption (Tmax = 6 hours) and increases bioavailability by approximately 50%. However, peak plasma concentrations after taking fluvastatin sodium extended-release tablets after a high-fat meal are lower than those after a single dose or twice-daily administration of 40 mg fluvastatin capsules. After oral administration, fluvastatin is primarily excreted via the intestines as metabolites (approximately 90%), with less than 2% remaining unchanged. Approximately 5% of the drug is recovered in the urine.
0.35 L/kg
0.8 L/h/kg
107 ± 38.1 L/h [Single dose of 20 mg for patients with hypercholesterolemia]
87.8 ± 45 L/h [Twice daily dose of 20 mg for patients with hypercholesterolemia]
108 ± 44.7 L/h [Single dose of 40 mg for patients with hypercholesterolemia]
64.2 ± 21.1 L/h [Twice daily dose of 40 mg for patients with hypercholesterolemia]
/Breast Milk/ According to animal studies, the concentration ratio of fluvastatin in breast milk to plasma is 2:1.
After oral administration of capsules, fluvastatin reaches peak plasma concentration within 1 hour. The absolute bioavailability after a 10 mg dose is 24% (range 9% to 50%).
Fluvastatin binds to plasma proteins at a rate of 98%. The average volume of distribution (VDss) is estimated to be 0.35 L/kg. At therapeutic concentrations, warfarin, salicylates, and glibenclamide do not affect the protein binding of fluvastatin. After fasting administration of fluvastatin sodium extended-release tablets (80 mg), peak plasma concentrations are reached in approximately 3 hours; after administration with a low-fat meal, peak plasma concentrations are reached in approximately 2.5 hours. Compared to fasting administration of immediate-release fluvastatin capsules, the mean relative bioavailability of the extended-release tablets is approximately 29% (range: 9% to 66%). High-fat meals delay absorption (time to peak: 6 hours) and increase the bioavailability of the extended-release tablets by approximately 50%. However, after administration of fluvastatin sodium extended-release tablets after a high-fat meal, the peak plasma concentration is lower than that after a single dose or twice-daily administration of 40 mg fluvastatin capsules. For more complete data on the absorption, distribution, and excretion of fluvastatin (8 types), please visit the HSDB records page.

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Metabolism/Metabolites
Fluvastatin is primarily metabolized in the liver via hydroxylation at the 5- and 6-positions of the indole ring, yielding 5-hydroxyfluvastatin and 6-hydroxyfluvastatin, respectively. Additionally, N-dealkylation to N-deisopropylfluvastatin and β-oxidation of the side chain occur. It is mainly metabolized via the CYP2C9 isoenzyme system (75%), followed by CYP3A4 (approximately 20%) and CYP2C8 (approximately 5%). Hydroxylated metabolites retain some pharmacological activity but exist in the blood as conjugates (glucuronide and sulfate) and are rapidly excreted into feces via bile. The two enantiomers of fluvastatin are metabolized similarly. Fluvastatin is also glucuronidated by the UGT enzyme. In vitro data indicate that the metabolism of fluvastatin involves multiple cytochrome P450 (CYP) isoenzymes. The CYP2C9 isoenzyme is primarily involved in the metabolism of fluvastatin (approximately 75%), while the involvement of CYP2C8 and CYP3A4 isoenzymes is much lower, at approximately 5% and 20%, respectively. Fluvastatin is metabolized in the liver, mainly through hydroxylation at the 5 and 6 positions of the indole ring. N-dealkylation and β-oxidation of the side chain also occur. The hydroxyl metabolite has some pharmacological activity but does not circulate in the blood. Fluvastatin has two enantiomers. The two enantiomers of fluvastatin are metabolized in a similar manner.

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Biological Half-Life
3 hours

The elimination half-life of fluvastatin is approximately 3 hours.
Fluvastatin is an orally active statin with favorable pharmacokinetic properties. It is rapidly absorbed after oral administration and undergoes extensive first-pass metabolism in the liver. In contrast to other statins, Fluvastatin does not appear to interact with other drugs that inhibit CYP3A4, which may reduce the risk of drug-drug interactions. The compound is metabolized primarily by CYP2C9. Its half-life is relatively short, supporting once-daily dosing. Fluvastatin's pharmacokinetic profile is well-characterized from its clinical use as a lipid-lowering agent.

Toxicity Summary
Identification and Use: Fluvastatin is a cholesterol-lowering drug and an hydroxymethylglutaryl-CoA reductase inhibitor. Human Exposure and Toxicity: Rhabdomyolysis has been reported with fluvastatin capsules and other drugs in the same class, leading to myoglobinuria and acute renal failure. Rare reports of fatal and non-fatal hepatic failure have been reported in patients taking statins, including fluvastatin. If severe liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during fluvastatin treatment, treatment should be discontinued immediately. Fluvastatin capsules are contraindicated in pregnant women or women who may become pregnant. Serum cholesterol and triglyceride levels are elevated during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Fluvastatin capsules may harm the fetus if taken by a pregnant woman. Adverse Reactions: Statin treatment may cause neuropsychiatric reactions. These adverse reactions include behavioral changes; cognitive and memory impairment; sleep disturbances; and sexual dysfunction. Animal studies: Carcinogenicity studies in mice (dose levels of 0.3, 15, and 30 mg/kg/day) showed a statistically significant increase in the incidence of forestomac squamous cell papillomas in both male and female mice at a dose of 30 mg/kg/day, similar to that in rats; a similar effect was observed in female mice at a dose of 15 mg/kg/day. Fluvastatin caused delayed skeletal development in rats at a dose of 12 mg/kg/day and in rabbits at a dose of 10 mg/kg/day. No mutagenicity was observed in the following in vitro studies, regardless of metabolic activation: microbial mutagenesis using mutant strains of Salmonella Typhimurium or Escherichia coli; malignant transformation of BALB/3T3 cells; unplanned DNA synthesis in primary rat hepatocytes; chromosomal aberrations in V79 Chinese hamster cells; and HGPRT V79 Chinese hamster cells. Furthermore, no evidence of in vivo mutagenicity was found in rat or mouse micronucleus assays.

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Hepatotoxicity
Fluvastatin treatment is associated with mild, asymptomatic, and usually transient elevations in serum transaminases in 1% to 5% of patients, but approximately 1% experience elevations exceeding three times the upper limit of normal. In a pooled analysis of large-scale prospective surveillance studies, up to 5% of patients experienced elevated ALT levels; among patients with ALT levels exceeding three times the upper limit of normal, the rate was 1.1% in the fluvastatin treatment group and 0.3% in the placebo group. These elevations are more common with high-dose fluvastatin treatment. Most of these elevations are self-limiting and do not require dose adjustment. Fluvastatin is the statin with the highest incidence of elevated serum transaminases and symptomatic liver injury, but significant, clinically visible liver injury caused by fluvastatin remains very rare, with an estimated incidence of 1.7 cases per 10,000 people-years. In the few reported cases, clinical injury usually appears within 1 to 4 months of starting treatment, and the injury pattern is usually cholestatic or mixed. Rash, fever, and eosinophilia are uncommon. At least one case with an autoimmune feature has been reported. Most cases resolve within months of onset. Rare cases of acute liver failure and death have been associated with fluvastatin. Probability score: B (likely a rare cause of clinically significant liver damage). Effects during pregnancy and lactation. Overview of medication use during lactation There is currently no published information on the use of fluvastatin during lactation. It is generally believed that fluvastatin should not be used during lactation due to concerns about disrupting the lipid metabolism of infants. However, it is also believed that children with homozygous familial hypercholesterolemia who have been treated with statins since 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 period of newborns or preterm infants, other medications may be preferred. Effects on breastfed infants No published information was found as of the revision date.
◉ Effects on Lactation and Breast Milk
As of the revision date, no relevant published information was found.

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Protein Binding
98% bound to plasma proteins. At therapeutic concentrations, the protein binding of fluvastatin is not affected by warfarin, salicylic acid, or glibenclamide.

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Drug Interactions
It has been reported that fluvastatin, when used in combination with colchicine, can cause myopathy, including rhabdomyolysis; therefore, caution should be exercised when prescribing fluvastatin in combination with colchicine.
It has been reported that bleeding and/or prolonged prothrombin time have occurred in patients taking coumarin anticoagulants who also take other HMG-CoA reductase inhibitors. Therefore, patients taking warfarin anticoagulants should be closely monitored for prothrombin time when starting fluvastatin sodium or changing the dose of fluvastatin sodium.
Concomitant use of fluvastatin with phenytoin sodium increases phenytoin sodium exposure. Patients should continue to be appropriately monitored when starting or adjusting the dose of fluvastatin. Concomitant use of fluvastatin with glibenclamide increases glibenclamide exposure. Patients taking both glibenclamide and fluvastatin should continue to be appropriately monitored. For more complete data on drug interactions with fluvastatin (14 items in total), please visit the HSDB record page.
Fluvastatin is a well-tolerated medication with a favorable safety profile. Common adverse effects include gastrointestinal disturbances, muscle pain, and elevated liver enzymes. As with other statins, Fluvastatin may cause myopathy and rhabdomyolysis, although this is rare. The compound is contraindicated in patients with active liver disease or hypersensitivity to statins. Its safety profile is well-established from extensive clinical use. Fluvastatin's lack of significant CYP3A4 interaction may offer an advantage over other statins in terms of drug-drug interaction potential.

[1]. Fluvastatin protects vascular smooth muscle cells against oxidative stress through the Nrf2-dependent antioxidant pathway. Atherosclerosis. 2010 Dec;213(2):377-84.

[2]. Fluvastatin, a lipophilic statin, induces apoptosis in human hepatocellular carcinoma cells through mitochondria-operated pathway. Indian J Exp Biol. 2010 Dec;48(12):1167-74.

Therapeutic Uses
Cholesterol-lowering drug; Hydroxymethylglutaryl-CoA reductase inhibitor
Fluvastatin capsules are indicated for: as adjunctive dietary therapy to lower total cholesterol (Total-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and apolipoprotein B (Apo B) levels, and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson type IIa and IIb); as adjunctive dietary therapy to lower total cholesterol (Total-C), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (Apo B) levels in adolescent boys and girls aged 10 to 16 years with heterozygous familial hypercholesterolemia who meet the following criteria at least one year after menarche: 1. LDL-C ≥ 190 mg/dL; or 2. LDL-C ≥ 160 mg/dL. mg/dL, and: have a family history of early-onset cardiovascular disease, or have two or more other cardiovascular disease risk factors. /US product label includes/
For patients with clinically diagnosed coronary heart disease (CHD), fluvastatin capsules are indicated for: reducing the risk of undergoing coronary revascularization surgery and slowing the progression of coronary atherosclerosis. /US product label includes/
Fluvastatin can reduce total cholesterol and LDL cholesterol levels in a small number of patients with dyslipidemia that is associated with or exacerbated by diabetes (diabetic dyslipidemia), renal insufficiency, heart or kidney transplantation, or nephrotic syndrome (nephrotic hyperlipidemia). Fluvastatin has also been shown to reduce proteinuria in patients with immunoglobulin A nephropathy. Further studies are needed to determine the role of fluvastatin treatment in these patients (if any). /US product label does not include/

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Drug Warning
Rhabdomyolysis and secondary myoglobinuria leading to acute renal failure have been reported after taking fluvastatin capsules and other drugs in the same class.
Rare post-marketing reports of fatal and non-fatal liver failure in patients taking statins (including fluvastatin) have emerged. If severe liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during fluvastatin sodium treatment, treatment should be discontinued immediately. Fluvastatin sodium should not be restarted unless another cause is identified.
Fluvastatin is excreted into animal milk. Because HMG-CoA reductase inhibitors can cause serious adverse reactions in nursing infants, women taking fluvastatin capsules should be advised not to breastfeed.
Fluvastatin capsules are contraindicated in pregnant women or women who may become pregnant. Serum cholesterol and triglyceride levels are elevated during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Taking fluvastatin capsules during pregnancy may harm the fetus. Atherosclerosis is a chronic process, and discontinuing lipid-lowering drugs during pregnancy has minimal impact on the long-term treatment efficacy of primary hypercholesterolemia. Fluvastatin capsules should only be given to women of childbearing age who are extremely unlikely to become pregnant and have been informed of the potential risks. If a patient becomes pregnant while taking this medication, fluvastatin capsules should be discontinued immediately, and the patient should be informed of the potential harm to the fetus. For more complete data on fluvastatin (24 total), please visit the HSDB records page. Pharmacodynamics: Fluvastatin is the first synthetic HMG-CoA reductase inhibitor. It is a hydrophilic acidic lipid-lowering drug used to reduce cholesterol and triglyceride levels associated with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson IIa and IIb), to slow the progression of coronary atherosclerosis in patients with coronary artery disease, and as a secondary prevention treatment for patients with coronary artery disease to reduce the risk of requiring coronary revascularization surgery. Although similar to lovastatin, simvastatin, and pravastatin, fluvastatin has a shorter half-life, no active metabolites, high protein binding, and extremely low cerebrospinal fluid permeability. Fluvastatin primarily works in the liver. It is composed of two racemic erythrostatin enantiomers, of which the 3R,5S enantiomer is the pharmacologically active.
Fluvastatin (CAS# 93957-54-1) is an antilipemic agent that competitively inhibits HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. It belongs to the statin class of medications and is used to reduce plasma cholesterol levels and prevent cardiovascular disease. In contrast to other statins, it does not appear to interact with other drugs that inhibit CYP3A4. Fluvastatin also exhibits antineoplastic properties and inhibits cell proliferation. The compound is for research use only and is not approved for human therapeutic use in many applications. It is a valuable tool for studying cholesterol metabolism and statin biology.

C24H26FNO4

411.46594

411.184

93957-54-1

Fluvastatin sodium;93957-55-2;Fluvastatin-d6 sodium;(3S,5R)-Fluvastatin-d6 sodium;2249799-35-5;(3R,5S)-Fluvastatin sodium;94061-80-0;(3S,5R)-Fluvastatin sodium;94061-81-1

446155

Light yellow to yellow solid powder

1.2±0.1 g/cm3

681.8±55.0 °C at 760 mmHg

194-197ºC

366.1±31.5 °C

0.0±2.2 mmHg at 25°C

1.587

3.62

3

5

8

30

590

2

CC(C)N1C2=CC=CC=C2C(=C1/C=C/[C@H](C[C@H](CC(=O)O)O)O)C3=CC=C(C=C3)F

FJLGEFLZQAZZCD-MCBHFWOFSA-N

InChI=1S/C24H26FNO4/c1-15(2)26-21-6-4-3-5-20(21)24(16-7-9-17(25)10-8-16)22(26)12-11-18(27)13-19(28)14-23(29)30/h3-12,15,18-19,27-28H,13-14H2,1-2H3,(H,29,30)/b12-11+/t18-,19-/m1/s1

(E,3R,5S)-7-[3-(4-fluorophenyl)-1-propan-2-ylindol-2-yl]-3,5-dihydroxyhept-6-enoic acid

Lescol, Canef, Vastin, Cranoc, XU 62320XU62320XU-62320

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

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

DMSO : ~5 mg/mL (~12.15 mM)

Solubility in Formulation 1: ≥ 0.5 mg/mL (1.22 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 5.0 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: ≥ 0.5 mg/mL (1.22 mM) (saturation unknown) in 10% DMSO + 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 5.0 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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 (Please use freshly prepared in vivo formulations for optimal results.)