Details
Stereochemistry | RACEMIC |
Molecular Formula | C24H26FNO4 |
Molecular Weight | 411.4659 |
Optical Activity | ( + / - ) |
Defined Stereocenters | 2 / 2 |
E/Z Centers | 1 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CC(C)N1C(\C=C\[C@H](O)C[C@H](O)CC(O)=O)=C(C2=C1C=CC=C2)C3=CC=C(F)C=C3
InChI
InChIKey=FJLGEFLZQAZZCD-JUFISIKESA-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-/m0/s1
Fluvastatin is an antilipemic agent that competitively inhibits hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase. Fluvastatin is marketed under the trade names Lescol, Canef, Vastin. LESCOL/LESCOL XL is an HMG-CoA reductase inhibitor (statin) indicated as
an adjunctive therapy to diet to:
Reduce elevated TC, LDL-C, Apo B, and TG, and to increase HDL-C in adult
patients with primary hypercholesterolemia and mixed dyslipidemia
Reduce elevated TC, LDL-C, and Apo B levels in boys and post-menarchal
girls, 10 to 16 years of age, with heterozygous familial hypercholesterolemia
after failing an adequate trial of diet therapy
Reduce the risk of undergoing revascularization procedures in patients with
clinically evident CHD
Slow the progression of atherosclerosis in patients with CHD.
Fluvastatin selectively and competitively inhibits the hepatic enzyme hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reductase is responsible for converting HMG-CoA to mevalonate, the rate-limiting step in cholesterol biosynthesis. Inhibition results in a decrease in hepatic cholesterol levels which stimulates the synthesis of LDL receptors and increases hepatic uptake of LDL cholesterol. The end result is decreased levels of plasma total and LDL cholesterol.
Originator
Sources: http://adisinsight.springer.com/drugs/800000409
Curator's Comment: # Novartis
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL402 |
28.0 nM [IC50] | ||
Target ID: CHEMBL4605 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15846457 |
337.0 µM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | LESCOL Approved UseLESCOL/LESCOL XL is an HMG-CoA reductase inhibitor (statin) indicated as
an adjunctive therapy to diet to:
Reduce elevated TC, LDL-C, Apo B, and TG, and to increase HDL-C in adult
patients with primary hypercholesterolemia and mixed dyslipidemia (1.1)
Reduce elevated TC, LDL-C, and Apo B levels in boys and post-menarchal
girls, 10 to 16 years of age, with heterozygous familial hypercholesterolemia
after failing an adequate trial of diet therapy (1.1)
Reduce the risk of undergoing revascularization procedures in patients with
clinically evident CHD (1.2)
Slow the progression of atherosclerosis in patients with CHD (1.2) Launch Date1993 |
|||
Primary | LESCOL Approved UseLESCOL/LESCOL XL is an HMG-CoA reductase inhibitor (statin) indicated as
an adjunctive therapy to diet to:
Reduce elevated TC, LDL-C, Apo B, and TG, and to increase HDL-C in adult
patients with primary hypercholesterolemia and mixed dyslipidemia (1.1)
Reduce elevated TC, LDL-C, and Apo B levels in boys and post-menarchal
girls, 10 to 16 years of age, with heterozygous familial hypercholesterolemia
after failing an adequate trial of diet therapy (1.1)
Reduce the risk of undergoing revascularization procedures in patients with
clinically evident CHD (1.2)
Slow the progression of atherosclerosis in patients with CHD (1.2) Launch Date1993 |
|||
Primary | LESCOL Approved UseLESCOL/LESCOL XL is an HMG-CoA reductase inhibitor (statin) indicated as
an adjunctive therapy to diet to:
Reduce elevated TC, LDL-C, Apo B, and TG, and to increase HDL-C in adult
patients with primary hypercholesterolemia and mixed dyslipidemia (1.1)
Reduce elevated TC, LDL-C, and Apo B levels in boys and post-menarchal
girls, 10 to 16 years of age, with heterozygous familial hypercholesterolemia
after failing an adequate trial of diet therapy (1.1)
Reduce the risk of undergoing revascularization procedures in patients with
clinically evident CHD (1.2)
Slow the progression of atherosclerosis in patients with CHD (1.2) Launch Date1993 |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
205 μg/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29368187 |
20 mg single, oral dose: 20 mg route of administration: Oral experiment type: SINGLE co-administered: |
FLUVASTATIN plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
206.2 μg × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29368187 |
20 mg single, oral dose: 20 mg route of administration: Oral experiment type: SINGLE co-administered: |
FLUVASTATIN plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
0.54 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29368187 |
20 mg single, oral dose: 20 mg route of administration: Oral experiment type: SINGLE co-administered: |
FLUVASTATIN plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
Doses
Dose | Population | Adverse events |
---|---|---|
640 mg 1 times / day multiple, oral Highest studied dose Dose: 640 mg, 1 times / day Route: oral Route: multiple Dose: 640 mg, 1 times / day Sources: Page: p.505 |
unhealthy, ADULT n = 7 Health Status: unhealthy Condition: lipid metabolism disorder Age Group: ADULT Sex: M+F Food Status: FED Population Size: 7 Sources: Page: p.505 |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Sources: https://pubmed.ncbi.nlm.nih.gov/8737761/ Page: 3.0 |
moderate [IC50 100 uM] | |||
no | ||||
no | ||||
no | ||||
not significant | ||||
weak [Ki 94.3 uM] | ||||
yes [IC50 20 uM] | ||||
yes [IC50 26.3 uM] | ||||
yes [IC50 5.79 uM] | ||||
yes [Ki 0.3 uM] | ||||
Sources: https://pubmed.ncbi.nlm.nih.gov/15955871/ Page: 5.0 |
yes [Ki 5.43 uM] | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/8937853/ |
yes |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
major | yes (co-administration study) Comment: Coadministration with rifampicin (CYP2C9 inducer) increased the CL/F of fluvastatin by 95% and to reduce AUC by 50%. |
|||
minor | ||||
minor | ||||
minor | ||||
minor | unknown (co-administration study) Comment: Coadministration with cyclocporine resulted in 3.1-fold increase in AUC; however, cannot be explained through these mechanisms, since neither pravastatin nor fluvastatin has been shown to be a substrate for either P-gp or CYP3A4; coadministration with itraconazole had no significant impact on Cmax and AUC of fluvastatin |
|||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
Sources: https://pubmed.ncbi.nlm.nih.gov/11368292/ Page: 14.0 |
no | unknown (co-administration study) Comment: Coadministration with cyclocporine resulted in 3.1-fold increase in AUC; however, cannot be explained through these mechanisms, since neither pravastatin nor fluvastatin has been shown to be a substrate for either P-gp or CYP3A4 Sources: https://pubmed.ncbi.nlm.nih.gov/11368292/ Page: 14.0 |
||
yes | ||||
yes | ||||
yes | unlikely (co-administration study) Comment: coadministered with rifampin. See https://pubmed.ncbi.nlm.nih.gov/29768081/. Pharmacogenomic study also performed. Not significant: see https://www.lipidjournal.com/article/S1933-2874(14)00072-5/pdf Sources: https://pubmed.ncbi.nlm.nih.gov/17470528/ |
|||
yes | yes (pharmacogenomic study) Comment: AUC of drug increased by 72% |
PubMed
Title | Date | PubMed |
---|---|---|
Synthesis and biological activity of new HMG-CoA reductase inhibitors. 3. Lactones of 6-phenoxy-3,5-dihydroxyhexanoic acids. | 1991 Oct |
|
Fluvastatin in combination with other lipid-lowering agents. | 1996 Jan |
|
Effect of fluvastatin or bezafibrate on the distribution of high density lipoprotein subpopulations in patients with familial hypercholesterolemia. | 1996 Sep |
|
A head-to-head comparison of the cost effectiveness of HMG-CoA reductase inhibitors and fibrates in different types of primary hyperlipidemia. | 1997 Jan |
|
Troglitazone upregulates LDL receptor activity in HepG2 cells. | 1998 Aug |
|
Postural hypotension induced by paroxetine. | 1998 Feb 21 |
|
[Cardiology in 1997]. | 1998 Oct 5 |
|
Statins and peripheral neuropathy. | 1999 Jan |
|
Effects of fluvastatin and bezafibrate combination on plasma fibrinogen, t-plasminogen activator inhibitor and C reactive protein levels in coronary artery disease patients with mixed hyperlipidaemia (FACT study). Fluvastatin Alone and in Combination Treatment. | 2000 Apr |
|
Does vitamin E beneficially affect muscle pains during HMG-Co-enzyme-A-reductase inhibitors without CK-elevation? | 2000 Mar |
|
Effect of fluvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on nitric oxide-induced hydroxyl radical generation in the rat heart. | 2001 Apr 30 |
|
Structural mechanism for statin inhibition of HMG-CoA reductase. | 2001 May 11 |
|
Fibrate and statin synergistically increase the transcriptional activities of PPARalpha/RXRalpha and decrease the transactivation of NFkappaB. | 2002 Jan 11 |
|
Valsartan therapy has additive anti-oxidative effect to that of fluvastatin therapy against low-density lipoprotein oxidation: studies in hypercholesterolemic and hypertensive patients. | 2002 Jul |
|
Statins and risk of polyneuropathy: a case-control study. | 2002 May 14 |
|
Molecular mechanism for inhibition of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase by rosuvastatin. | 2003 Jun |
|
Regional intestinal absorption and biliary excretion of fluvastatin in the rat: possible involvement of mrp2. | 2004 Sep-Oct |
|
In vitro and pharmacophore-based discovery of novel hPEPT1 inhibitors. | 2005 Apr |
|
Effect of atorvastatin and fluvastatin on the metabolism of midazolam by cytochrome P450 in vitro. | 2005 Aug |
|
Bile salt export pump (BSEP/ABCB11) can transport a nonbile acid substrate, pravastatin. | 2005 Aug |
|
Prediction of CYP2C9-mediated drug-drug interactions: a comparison using data from recombinant enzymes and human hepatocytes. | 2005 Nov |
|
Focal seizures after treatment with fluvastatin in a patient with a history of catastrophic antiphospholipid syndrome. | 2005 Nov 15 |
|
Human hepatobiliary transport of organic anions analyzed by quadruple-transfected cells. | 2005 Oct |
|
Binding thermodynamics of statins to HMG-CoA reductase. | 2005 Sep 6 |
|
Chiral evaluation of fluvastatin in human plasma by high-performance liquid chromatography electrospray mass spectrometry. | 2006 Mar 7 |
|
Cardioprotective effect of fluvastatin on isoproterenol-induced myocardial infarction in rat. | 2008 May 31 |
|
Roles of different CYP enzymes in the formation of specific fluvastatin metabolites by human liver microsomes. | 2009 Nov |
|
In vitro interactions between primycin and different statins in their effects against some clinically important fungi. | 2010 Feb |
|
A gene score of nine LDL and HDL regulating genes is associated with fluvastatin-induced cholesterol changes in women. | 2010 Mar |
|
Effect of an antimicrobial agent on atherosclerotic plaques: assessment of metalloproteinase activity by molecular imaging. | 2010 Mar 23 |
|
The phototoxicity of fluvastatin, an HMG-CoA reductase inhibitor, is mediated by the formation of a benzocarbazole-like photoproduct. | 2010 Nov |
|
Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. | 2015 May 18 |
Sample Use Guides
In Vivo Use Guide
Sources: https://www.drugs.com/dosage/fluvastatin.html
Usual Adult Dose for Hyperlipidemia
Immediate Release Capsules:
-Low-density lipoprotein cholesterol (LDL-C) reduction to a goal of 25% or greater: Initial dose of 40 mg orally once a day in the evening or 40 mg orally twice a day
-LDL-C reduction to a goal of less than 25%: Initial dose of 20 mg orally once a day
-Maintenance dose: 20 mg to 80 mg per day
Usual Adult Dose for Hyperlipoproteinemia Type IIa (Elevated LDL)
Immediate Release Capsules:
-Low-density lipoprotein cholesterol (LDL-C) reduction to a goal of 25% or greater: Initial dose of 40 mg orally once a day in the evening or 40 mg orally twice a day
-LDL-C reduction to a goal of less than 25%: Initial dose of 20 mg orally once a day
-Maintenance dose: 20 mg to 80 mg per day
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/11273020
Fluvastatin markedly inhibits the formation of thiobarbituric acid reactive substances in iron (II)-supported peroxidation of liposomes with IC50 of 12 uM. Fluvastatin ranging from 1 uM to 100 uM inhibits peroxyl radical-mediated peroxidation of liposomes induced by water-soluble and lipid-soluble radical generators, 2,2'-azobis (2-amidinopropane) dihydro-chloride and 2,2'-azobis (2,4-dimethylvaleronitrile), respectively.
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Classification Tree | Code System | Code | ||
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WHO-VATC |
QC10AA04
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NDF-RT |
N0000175589
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LIVERTOX |
NBK548435
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NDF-RT |
N0000000121
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NCI_THESAURUS |
C1655
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WHO-ATC |
C10AA04
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41127
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CHEMBL2220442
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Fluvastatin
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FLUVASTATIN
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ACTIVE MOIETY
SALT/SOLVATE (PARENT)