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Identification
NameFluticasone furoate
Accession NumberDB08906
TypeSmall Molecule
GroupsApproved
Description

Fluticasone furoate is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. Despite the similarity in the names, fluticasone furoate and fluticasone propionate are different drugs with different properties. It is marketed under the brand name, Veramyst in the US by GlaxoSmithKline for the management of chronic obstructive pulmonary disease (COPD). FDA approved on April 27, 2007.

Fluticasone furoate is available as a combination product with vilanterol, a long-acting beta-2 agonist, under the tradename Breo Ellipta. Approved by the FDA in 2013, its use is indicated for the long-term, once-daily maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and emphysema. It is also indicated for once-daily maintenance treatment of asthma in patients aged 18 or older with reversible obstructive airways disease.

Structure
Thumb
Synonyms
Fluticasonum furoas
Furoate de fluticasone
Furoato de fluticasona
External Identifiers
  • GSK 685698
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Arnuity Elliptapowder100 mcginhalation; oralGlaxosmithkline Inc2016-01-26Not applicableCanada
Arnuity Elliptapowder200 mcginhalation; oralGlaxosmithkline Inc2015-12-14Not applicableCanada
Arnuity Elliptapowder200 ug/1respiratory (inhalation)Glaxo Smith Kline Llc2014-08-20Not applicableUs
Arnuity Elliptapowder100 ug/1respiratory (inhalation)Glaxo Smith Kline Llc2014-08-20Not applicableUs
Avamysspray, metered dose27.5 mcgnasalGlaxosmithkline Inc2007-10-22Not applicableCanada
Veramystspray, metered27.5 ug/1nasalGlaxo Smith Kline Llc2007-05-15Not applicableUs
Veramystspray, metered27.5 ug/1nasalPhysicians Total Care, Inc.2010-09-07Not applicableUs
Veramystspray, metered27.5 ug/1nasalREMEDYREPACK INC.2013-06-07Not applicableUs
Veramystspray, metered27.5 ug/1nasalLake Erie Medical & Surgical Supply DBA Quality Care Products LLC2007-05-15Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixtures
NameLabellerIngredients
Breo ElliptaGlaxo Smith Kline Llc
SaltsNot Available
Categories
UNIIJS86977WNV
CAS number397864-44-7
WeightAverage: 538.576
Monoisotopic: 538.163693965
Chemical FormulaC27H29F3O6S
InChI KeyInChIKey=XTULMSXFIHGYFS-VLSRWLAYSA-N
InChI
InChI=1S/C27H29F3O6S/c1-14-9-16-17-11-19(29)18-10-15(31)6-7-24(18,2)26(17,30)21(32)12-25(16,3)27(14,23(34)37-13-28)36-22(33)20-5-4-8-35-20/h4-8,10,14,16-17,19,21,32H,9,11-13H2,1-3H3/t14-,16+,17+,19+,21+,24+,25+,26+,27+/m1/s1
IUPAC Name
(1R,2S,8S,10S,11S,13R,14R,15S,17S)-1,8-difluoro-14-{[(fluoromethyl)sulfanyl]carbonyl}-17-hydroxy-2,13,15-trimethyl-5-oxotetracyclo[8.7.0.0²,⁷.0¹¹,¹⁵]heptadeca-3,6-dien-14-yl furan-2-carboxylate
SMILES
[H][C@@]12C[C@@H](C)[C@](OC(=O)C3=CC=CO3)(C(=O)SCF)[C@@]1(C)C[[email protected]](O)[C@@]1(F)[C@@]2([H])C[[email protected]](F)C2=CC(=O)C=C[C@]12C
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as steroid esters. These are compounds containing a steroid moiety which bears a carboxylic acid ester group.
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassSteroids and steroid derivatives
Sub ClassSteroid esters
Direct ParentSteroid esters
Alternative Parents
Substituents
  • Steroid ester
  • Androgen-skeleton
  • Androstane-skeleton
  • 11-hydroxysteroid
  • 11-beta-hydroxysteroid
  • Oxosteroid
  • Hydroxysteroid
  • Halo-steroid
  • 6-halo-steroid
  • 9-halo-steroid
  • 3-oxosteroid
  • 3-oxo-delta-1,4-steroid
  • Delta-1,4-steroid
  • Furoate
  • Heteroaromatic compound
  • Furan
  • Cyclic alcohol
  • Cyclic ketone
  • Thiocarboxylic acid ester
  • Secondary alcohol
  • Ketone
  • Halohydrin
  • Fluorohydrin
  • Carboxylic acid ester
  • Oxacycle
  • Organoheterocyclic compound
  • Sulfenyl compound
  • Thioether
  • Thiocarboxylic acid or derivatives
  • Monocarboxylic acid or derivatives
  • Carboxylic acid derivative
  • Halomethane
  • Hydrocarbon derivative
  • Organosulfur compound
  • Organooxygen compound
  • Organofluoride
  • Organohalogen compound
  • Carbonyl group
  • Alkyl halide
  • Alkyl fluoride
  • Alcohol
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationFluticasone furoate nasal spray is indicated for the treatment of the symptoms of seasonal and perennial allergic rhinitis in patients aged 2 years and older. Breo Ellipta, a mixture of fluticasone furoate and vilanterol is indicated for the long-term, once-daily maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and emphysema. It is also indicated for once-daily maintenance treatment of asthma in patients aged 18 or older with reversible obstructive airways disease. Breo Ellipta should not be used for the relief of acute symptoms of asthma or COPD.
PharmacodynamicsFluticasone furoate binds to human glucocorticoid receptor more potently than dexamethasone (29.9-times) and fluticasone propionate (1.7-times). It also is highly retained in respiratory tissue. The significance of this finding is that fluticasone furoate may have a more pronounced and prolonged anti-inflammatory effect, which allows for once-daily dosing. It does not have any effect on the QTc interval. Furthermore, fluticasone furoate was not found to affect the hypothalamic-pituitary-adrenal axis function in adolescent and adult asthma.
Mechanism of actionFluticasone furoate is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. The precise mechanism through which fluticasone furoate affects rhinitis symptoms is not known. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. Specific effects of fluticasone furoate demonstrated in in vitro and in vivo models included activation of the glucocorticoid response element, inhibition of pro-inflammatory transcription factors such as NFkB, and inhibition of antigen-induced lung eosinophilia in sensitized rats. Fluticasone is also found to increase airway retention of long-acting beta adrenergic agonist, thus potentiating its beneficial effects for the treatment of asthma.
Related Articles
AbsorptionFollowing intranasal administration of fluticasone furoate, most of the dose is eventually swallowed and undergoes incomplete absorption and extensive first-pass metabolism in the liver and gut, resulting in negligible systemic exposure. Even at the highest recommended intranasal dose of 110 mcg once daily, plasma concentrations were not quantifiable. This is an especially useful feature as it lowers the incidence of adverse events associated with corticosteroid use. If administered using oral solution and intravenous dosing, 30% of the drug is absorbed and rapidly cleared from the plasma. Absolute bioavailability, intranasal route = 0.5%; Absolute bioavailability, oral route = 1.26%; Mean lung absorption time = 7 hours (regardless of formulation);
Volume of distribution

Steady state, IV administration = 608 L

Protein binding>99% protein bound.
Metabolism

Fluticasone furoate does not undergo cleavage into its two separate components, fluticasone and the furoate moiety. It undergoes extensive hepatic metabolism via CYP3A4. The principal route of metabolism is hydrolysis of the S-fluoromethyl carbothioate function to form the inactive 17β-carboxylic acid metabolite. Studies suggest that enterocytes may be involved in the metabolism of unabsorbed drug.

Route of eliminationFluticasone furoate and its metabolites are eliminated primarily in the feces, accounting for approximately 101% and 90% of the orally and intravenously administered dose, respectively. Urinary excretion accounted for approximately 1% and 2% of the orally and intravenously administered dose, respectively. Fluticasone furoate is extensively metabolized so very little is excreted unchanged.
Half lifeElimination phase half-life, IV dose = 15.1 hours; Elimination phase half-life, inhaled = 17 - 24 hours;
Clearance

Total plasma clearance = 58.7 L/h

ToxicityThe most common adverse reactions (>1% incidence) included headache, epistaxis, pharyngolaryngeal pain, nasal ulceration, back pain, pyrexia, and cough.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9917
Blood Brain Barrier+0.9666
Caco-2 permeable-0.5222
P-glycoprotein substrateSubstrate0.7675
P-glycoprotein inhibitor IInhibitor0.784
P-glycoprotein inhibitor IIInhibitor0.604
Renal organic cation transporterNon-inhibitor0.8329
CYP450 2C9 substrateNon-substrate0.8023
CYP450 2D6 substrateNon-substrate0.8893
CYP450 3A4 substrateSubstrate0.7205
CYP450 1A2 substrateNon-inhibitor0.6493
CYP450 2C9 inhibitorNon-inhibitor0.7288
CYP450 2D6 inhibitorNon-inhibitor0.8305
CYP450 2C19 inhibitorNon-inhibitor0.6388
CYP450 3A4 inhibitorInhibitor0.9211
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.69
Ames testNon AMES toxic0.747
CarcinogenicityNon-carcinogens0.9079
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.6232 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9787
hERG inhibition (predictor II)Non-inhibitor0.566
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Powderinhalation; oral100 mcg
Powderinhalation; oral200 mcg
Powderrespiratory (inhalation)100 ug/1
Powderrespiratory (inhalation)200 ug/1
Spray, metered dosenasal27.5 mcg
Powderinhalation
Powderrespiratory (inhalation)
Spray, meterednasal27.5 ug/1
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5873360 No1996-02-232016-02-23Us
US6537983 No2001-08-032021-08-03Us
US6759398 No2001-08-032021-08-03Us
US6858596 No2001-08-032021-08-03Us
US6878698 No2001-08-032021-08-03Us
US7101866 No2001-08-032021-08-03Us
US7439393 No2002-09-112022-09-11Us
US7541350 No2001-08-032021-08-03Us
US7629335 No2001-08-032021-08-03Us
US7776895 No2002-09-112022-09-11Us
US8062264 No2006-04-052026-04-05Us
US8113199 No2007-10-232027-10-23Us
US8147461 No2008-10-152028-10-15Us
US8161968 No2008-02-052028-02-05Us
US8201556 No2009-02-052029-02-05Us
US8347879 No2008-07-152028-07-15Us
US8511304 No2007-06-142027-06-14Us
US8534281 No2009-08-102029-08-10Us
US8746242 No2010-10-112030-10-11Us
US8752543 No2006-04-052026-04-05Us
USRE44874 No2003-03-232023-03-23Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
water solubilityInsoluble FDA label
pKa6 FDA label
Predicted Properties
PropertyValueSource
Water Solubility0.0434 mg/mLALOGPS
logP3.73ALOGPS
logP4.13ChemAxon
logS-4.1ALOGPS
pKa (Strongest Acidic)13.56ChemAxon
pKa (Strongest Basic)-3.4ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area93.81 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity130.08 m3·mol-1ChemAxon
Polarizability51.55 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Adrienne KOVACSNE-MEZEI, Roman Gabriel, Alexandr Jegorov, “POLYMORPHS OF FLUTICASONE FUROATE AND PROCESSES FOR PREPARATION THEREOF.” U.S. Patent US20100240629, issued September 23, 2010.

US20100240629
General References
  1. Allen A, Schenkenberger I, Trivedi R, Cole J, Hicks W, Gul N, Jacques L: Inhaled fluticasone furoate/vilanterol does not affect hypothalamic-pituitary-adrenal axis function in adolescent and adult asthma: randomised, double-blind, placebo-controlled study. Clin Respir J. 2013 Oct;7(4):397-406. doi: 10.1111/crj.12026. Epub 2013 Jun 5. [PubMed:23578031 ]
  2. Tamm M, Richards DH, Beghe B, Fabbri L: Inhaled corticosteroid and long-acting beta2-agonist pharmacological profiles: effective asthma therapy in practice. Respir Med. 2012 Dec;106 Suppl 1:S9-19. doi: 10.1016/S0954-6111(12)70005-7. [PubMed:23273165 ]
  3. Allen A, Bareille PJ, Rousell VM: Fluticasone furoate, a novel inhaled corticosteroid, demonstrates prolonged lung absorption kinetics in man compared with inhaled fluticasone propionate. Clin Pharmacokinet. 2013 Jan;52(1):37-42. doi: 10.1007/s40262-012-0021-x. [PubMed:23184737 ]
External Links
ATC CodesR01AD12R03AK10R03BA09
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (469 KB)
MSDSDownload (70.2 KB)
Interactions
Drug Interactions
Drug
AldesleukinFluticasone furoate may decrease the antineoplastic activities of Aldesleukin.
CeritinibFluticasone furoate may increase the hyperglycemic activities of Ceritinib.
CobicistatThe serum concentration of Fluticasone furoate can be increased when it is combined with Cobicistat.
Corticorelin ovine triflutateThe therapeutic efficacy of Corticorelin can be decreased when used in combination with Fluticasone furoate.
DeferasiroxThe risk or severity of adverse effects can be increased when Fluticasone furoate is combined with Deferasirox.
HyaluronidaseThe therapeutic efficacy of Hyaluronidase can be decreased when used in combination with Fluticasone furoate.
NelfinavirThe serum concentration of Fluticasone furoate can be increased when it is combined with Nelfinavir.
RitonavirThe serum concentration of Fluticasone furoate can be increased when it is combined with Ritonavir.
TelaprevirThe serum concentration of Fluticasone furoate can be increased when it is combined with Telaprevir.
TipranavirThe serum concentration of Fluticasone furoate can be increased when it is combined with Tipranavir.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
agonist
General Function:
Zinc ion binding
Specific Function:
Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon grow...
Gene Name:
NR3C1
Uniprot ID:
P04150
Molecular Weight:
85658.57 Da
References
  1. FDA label

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. FDA label

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Xenobiotic-transporting atpase activity
Specific Function:
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name:
ABCB1
Uniprot ID:
P08183
Molecular Weight:
141477.255 Da
References
  1. Hughes SC, Shardlow PC, Hollis FJ, Scott RJ, Motivaras DS, Allen A, Rousell VM: Metabolism and disposition of fluticasone furoate, an enhanced-affinity glucocorticoid, in humans. Drug Metab Dispos. 2008 Nov;36(11):2337-44. doi: 10.1124/dmd.108.022137. Epub 2008 Aug 11. [PubMed:18694910 ]
Comments
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Drug created on June 16, 2013 17:03 / Updated on May 24, 2016 02:08