FLUVASTATIN

Details

Stereochemistry	RACEMIC
Molecular Formula	C24H26FNO4
Molecular Weight	411.4668
Optical Activity	( + / - )
Defined Stereocenters	2 / 2
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC(C)n1c2ccccc2c(-c3ccc(cc3)F)c1/C(/[H])=C(\[H])/[C@@]([H])(C[C@@]([H])(CC(=O)O)O)O

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

HIDE SMILES / InChI

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021192s019lbl.pdf | https://www.drugbank.ca/drugs/DB01095

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

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
HMG-CoA reductase 39 Target ID: CHEMBL402 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021192s019lbl.pdf \| https://www.ncbi.nlm.nih.gov/pubmed/10965989	Inhibitor 7709		28.0 nM [IC50]
Oligopeptide transporter small intestine isoform 5 Target ID: CHEMBL4605 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15846457	Inhibitor 7709		337.0 µM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Hypercholesterolemia 46 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021192s019lbl.pdf	Primary	Approved 8003	LESCOL Approved Use 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 (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 Date 7.5729601E11
Atherosclerosis 70 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021192s019lbl.pdf	Primary	Approved 8003	LESCOL Approved Use 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 (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 Date 7.5729601E11
Dyslipidemia 28 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021192s019lbl.pdf	Primary	Approved 8003	LESCOL Approved Use 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 (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 Date 7.5729601E11

C_max

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

T_1/2

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: https://pubmed.ncbi.nlm.nih.gov/11336101 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: https://pubmed.ncbi.nlm.nih.gov/11336101 Page: p.505	Sources: https://pubmed.ncbi.nlm.nih.gov/11336101 Page: p.505

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1603 inhibitor 1461	substrate 944 inhibitor 1605	substrate 1116 inhibitor 1701

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1386 CYP2C19 1324 CYP3A 191 CYP2C8 818 P-gp 1344 BCRP 654 OAT3 591 OAT1 564	CYP1A2 971 CYP2A6 482 CYP2B6 616 CYP2C19 911 CYP2E1 604 CYP3A5 372 CYP1A1 323 CYP2C8 645 P-gp 1399 BCRP 506 OATP1B1 369 OATP2B1 97 OATP1B3 319	CYP1A1 106

Drug as perpetrator

Target	Modality	Activity
CYP2D6 1735	inhibitor 3041 Sources: https://pubmed.ncbi.nlm.nih.gov/8737761/ Page: 3.0	moderate [IC50 100 uM]
CYP1A2 1532	inhibitor 3041 Sources: https://dmd.aspetjournals.org/content/27/3/410.abstract	no
CYP2C19 1394	inhibitor 3041 Sources: https://dmd.aspetjournals.org/content/27/3/410.abstract	no
CYP3A 269	inhibitor 3041 Sources: https://dmd.aspetjournals.org/content/27/3/410.abstract	no
P-gp 1519	inhibitor 3041 Sources: https://pubmed.ncbi.nlm.nih.gov/17064205/	not significant
CYP3A4 1768	inhibitor 3041 Sources: https://associationofanaesthetists-publications.onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2044.2005.04110.x	weak [Ki 94.3 uM]
CYP2C8 868	inhibitor 3041 Sources: https://dmd.aspetjournals.org/content/27/3/410.abstract	yes [IC50 20 uM]
OAT1 568	inhibitor 3041 Sources: https://pubmed.ncbi.nlm.nih.gov/14729100/	yes [IC50 26.3 uM]
OAT3 593	inhibitor 3041 Sources: https://pubmed.ncbi.nlm.nih.gov/14729100/	yes [IC50 5.79 uM]
CYP2C9 1652	inhibitor 3041 Sources: https://dmd.aspetjournals.org/content/27/3/410.abstract	yes [Ki 0.3 uM]
BCRP 723	inhibitor 3041 Sources: https://pubmed.ncbi.nlm.nih.gov/15955871/ Page: 5.0	yes [Ki 5.43 uM]
CYP1A1 199	inducer 1443 Sources: https://pubmed.ncbi.nlm.nih.gov/8937853/	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP2C9 944	substrate 3107 Sources: https://dmd.aspetjournals.org/content/27/3/410.abstract	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%. Sources: https://dmd.aspetjournals.org/content/27/3/410.abstract
CYP1A1 323	substrate 3107 Sources: https://dmd.aspetjournals.org/content/27/3/410.abstract	minor
CYP2C8 645	substrate 3107 Sources: https://dmd.aspetjournals.org/content/27/3/410.abstract	minor
CYP2D6 1116	substrate 3107 Sources: https://dmd.aspetjournals.org/content/27/3/410.abstract	minor
CYP3A4 1603	substrate 3107 Sources: https://dmd.aspetjournals.org/content/27/3/410.abstract; https://pubmed.ncbi.nlm.nih.gov/17064205/	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 Sources: https://dmd.aspetjournals.org/content/27/3/410.abstract; https://pubmed.ncbi.nlm.nih.gov/17064205/
CYP1A2 971	substrate 3107 Sources: https://dmd.aspetjournals.org/content/27/3/410.abstract	no
CYP2A6 482	substrate 3107 Sources: https://dmd.aspetjournals.org/content/27/3/410.abstract	no
CYP2B6 616	substrate 3107 Sources: https://dmd.aspetjournals.org/content/27/3/410.abstract	no
CYP2C19 911	substrate 3107 Sources: https://dmd.aspetjournals.org/content/27/3/410.abstract	no
CYP2E1 604	substrate 3107 Sources: https://dmd.aspetjournals.org/content/27/3/410.abstract	no
CYP3A5 372	substrate 3107 Sources: https://dmd.aspetjournals.org/content/27/3/410.abstract	no
P-gp 1399	substrate 3107 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
OATP1B3 319	substrate 3107 Sources: https://pubmed.ncbi.nlm.nih.gov/17470528/	yes
OATP2B1 97	substrate 3107 Sources: https://pubmed.ncbi.nlm.nih.gov/17470528/	yes
OATP1B1 369	substrate 3107 Sources: https://pubmed.ncbi.nlm.nih.gov/17470528/	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/
BCRP 506	substrate 3107 Sources: https://www.jpharmsci.org/article/S0022-3549(16)30083-1/pdf	yes	yes (pharmacogenomic study) Comment: AUC of drug increased by 72% Sources: https://www.jpharmsci.org/article/S0022-3549(16)30083-1/pdf

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:38561	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:38561
ChemicalBook	CB03386396	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB03386396
MolPort	MolPort-006-167-704	https://www.molport.com/shop/molecule-link/MolPort-006-167-704
ZINC	ZINC000001530639	http://zinc15.docking.org/substances/ZINC000001530639
eMolecules	10141252	https://www.emolecules.com/cgi-bin/more?vid=10141252

PubMed

Title	Date	PubMed
Troglitazone upregulates LDL receptor activity in HepG2 cells.	1998 Aug	9703316
Postural hypotension induced by paroxetine.	1998 Feb 21	9518913
[Cardiology in 1997].	1998 Oct 5	9818470
Statin + fibrate combination therapy fluvastatin with bezafibrate or ciprofibrate in high risk patients with vascular disease.	1999 Jun 1	10402106
Enhancement of low density lipoprotein catabolism by non-steroidal anti-inflammatory drugs in cultured HepG2 cells.	1999 May 21	10395027
A HMG-CoA reductase inhibitor possesses a potent anti-atherosclerotic effect other than serum lipid lowering effects--the relevance of endothelial nitric oxide synthase and superoxide anion scavenging action.	2001 Apr	11254905
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	11335104
Preclinical and clinical pharmacology of Rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor.	2001 Mar 8	11256847
Structural mechanism for statin inhibition of HMG-CoA reductase.	2001 May 11	11349148
Fibrate and statin synergistically increase the transcriptional activities of PPARalpha/RXRalpha and decrease the transactivation of NFkappaB.	2002 Jan 11	11779144
Molecular mechanism for inhibition of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase by rosuvastatin.	2003 Jun	12773150
Expression of serum and glucocorticoid-inducible kinase1 in diabetic rats and its modulation by fluvastatin.	2005	16696316
In vitro and pharmacophore-based discovery of novel hPEPT1 inhibitors.	2005 Apr	15846457
Human hepatobiliary transport of organic anions analyzed by quadruple-transfected cells.	2005 Oct	16046661
Effects of chronic treatment with statins and fenofibrate on rat skeletal muscle: a biochemical, histological and electrophysiological study.	2006 Dec	17031388
Inhibitors of the mevalonate pathway as potential therapeutic agents in multiple myeloma.	2007 Mar	16996129
Pretreatment with statin attenuates the cardiotoxicity of Doxorubicin in mice.	2009 Jan 15	19147586
Roles of different CYP enzymes in the formation of specific fluvastatin metabolites by human liver microsomes.	2009 Nov	19663817
In vitro interactions between primycin and different statins in their effects against some clinically important fungi.	2010 Feb	19875509
Effects of add-on fluvastatin therapy in patients with chronic proteinuric nephropathy on dual renin-angiotensin system blockade: the ESPLANADE trial.	2010 Nov	20671225
Statins alter the hepatobiliary transport of unconjugated and conjugated bilirubin in sandwich-cultured rat hepatocytes.	2014 Sep	24909372
Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis.	2015 May 18	25811541

Patents

Sample Use Guides

In Vivo Use Guide

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

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.

Name

Type

Language

FLUVASTATIN

Official Name

English

FLUVASTATIN [WHO-DD]

Common Name

English

FLUVASTATIN [VANDF]

Common Name

English

FLUVASTATIN [MI]

Common Name

English

NSC-758896

Code

English

FLUVAS

Brand Name

English

FLUVASTATIN [INN]

Common Name

English

6-HEPTENOIC ACID, 7-(3-(4-FLUOROPHENYL)-1-(1-METHYLETHYL)-1H-INDOL-2-YL)-3,5-DIHYDROXY-, (3R,5S,6E)-REL-

Systematic Name

English

Classification Tree Code System Code

WHO-VATC

QC10AA04