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.

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.

[1]. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (fluvastatin) decreases inflammatory angiogenesis in mice. APMIS. 2012 24.

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

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

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.

C24H26FNO4

411.47

433.167

155229-75-7

(3R,5S)-Fluvastatin sodium;94061-80-0

446155

Typically exists as solid at room temperature

1.23

681.8ºC at 760 mmHg

194-197 °C
MW: 433.46. White to pale yellow powder. Hygroscopic. MP: 194-197 °C. Soluble in water, ethanol, methanol /Fluvastatin sodium salt/

366.1ºC

3.293

3

5

8

30

590

2

OC(C[C@@H](C[C@@H](/C=C/C1N(C(C)C)C2C=CC=CC=2C=1C1C=CC(F)=CC=1)O)O)=O

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

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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