Corticosteroid (Kd = 0.3 nM)
Glucocorticoid receptor [1]

By means of a metered atomizing spray pump, fluticasone furoate is applied locally to the nasal mucosa as an aqueous suspension of micronized fluticasone furoate in the form of a nasal spray [1]. Inappropriate stimulation of cultured human lung epithelial cells can be efficiently prevented by fluticasone furoate [1].

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In vitro studies showed that fluticasone furoate displayed high selectivity for the glucocorticoid receptor and had greater relative receptor affinity (2989, relative to dexamethasone) compared to other corticosteroids such as mometasone furoate, fluticasone propionate, beclomethasone-17-monopropionate, and budesonide. [1]
Fluticasone furoate exhibited greater potency than other corticosteroids in inhibiting tumor necrosis factor synthesis and action in vitro. [1]
It was also more potent in preventing damage to cultured human lung epithelial cells induced by different stimuli. [1]

In vitro, fluticasone furoate is 99.4% bound to oxidants, and additional research has demonstrated that the drug's effects are wide-ranging when it is absorbed. Because only unbound oxidant medications are able to act at the receptor site, proteins are extremely important. Fluticasone furoate is primarily cleared from the body by cytochrome P450 isoenzyme (CYP) 3A4, which processes the medication and transforms it into 17β-sulfamate (M10), a drug that effectively binds to the hypoglycemic hormone receptor. ..Only a small amount of fluticasone furoate is excreted in the feces, which is where it is mostly excreted [1].

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In multiple double-blind, placebo-controlled clinical trials involving patients with seasonal or perennial allergic rhinitis, once-daily intranasal fluticasone furoate (at a dose of 110 µg for adults/adolescents) was superior to placebo in reducing both nasal and ocular symptoms. Significant improvements were observed in reflective and instantaneous total nasal symptom scores (rTNSS, iTNSS) and total ocular symptom scores (rTOSS, iTOSS). [1]
In a dose-ranging study in seasonal allergic rhinitis patients, the 110 µg dose provided the optimal benefit-risk ratio. A statistically significant difference compared to placebo was first noted at 24 hours after the first dose for instantaneous total nasal symptom score. [1]
A study assessing short-term lower-leg growth rate in children with allergic rhinitis treated with fluticasone furoate nasal spray found no effect on growth rate, as measured by knemometry. [1]
Long-term (12-month) treatment with fluticasone furoate in adults and adolescents was well-tolerated, with no evidence of clinically relevant systemic corticosteroid exposure. [1]

Fluticasone furonate has high receptor affinity, with low equilibrium dissociation constant (kd = 0.3 nmol/L) and with greater relative receptor affinity (2989) than mometasone furoate (2244), fluticasone propionate (1775), beclomethasone-17-monopropionate (1345), ciclesonide active principle (1212), and budesonide (855)[1].
Some in vitro studies showed that FF displayed greater potency than other corticosteroids in inhibiting tumor necrosis factor synthesis and action. It was also more potent in preventing damage to cultured human lung epithelial cells by different stimulus. Experimental studies demonstrated more potent and faster anti-inflammatory activity of FF than fluticasone propionate[1].

Asthma is a complex disease with diverse clinical manifestations ranging from mild to severe. Despite existing guidelines for asthma recognition and treatment, still a proportion of patients stay uncontrolled. Combinational therapy which comprises inhaled corticosteroids (ICS) and a long acting B2 adrenreceptor agonist (LABA) has been suggested to control asthma. In this study T-bet expression was attested in CD4 T cells treated with Fluticasone Furoate (FF), Vilanterol (V) and FF/V combination in severe asthmatic patients compared to patients with moderate asthma and healthy controls using Immunocytochemistry (ICC). First, CD4 T cells were isolated from PBMCs of 12 patients and controls using CD4 T cell isolation kit. Subsequently, isolated CD4 T cells were cultured with FF, V and FF/V for 1 h. To accomplish ICC, cells were incubated with anti-T-bet antibody, and then stained with HRP-bound secondary antibody. T-bet expression was evaluated using light microscopy. Statistical analyses were performed using R 3.5.2 software and visualized by ggplot2 3.1.0 package. Significant increasing in T-bet expression was seen in CD4 T cells from patients with moderate asthma treated with FF and FF/V. Suggesting conclusion would be distinct mechanisms responsible for severe asthma and moderate asthma in the patients and the needs for novel therapies. Further molecular studies in different asthma phenotypes would be instructive for asthma treatment [2].

Allergic rhinitis (AR) is a prevalent disease with great morbidity and significant societal and economic burden. Intranasal corticosteroids are recommended as first-line therapy for patients with moderate-to-severe disease, especially when nasal congestion is a major component of symptoms. To compare the efficacy and safety profile of different available intranasal corticosteroids for the treatment of AR, it is important to understand their different structures and pharmacokinetic and pharmacodynamic properties. Knowledge of these drugs has increased tremendously over the last decade. Studies have elucidated mechanisms of action, pharmacologic properties, and the clinical impact of these drugs in allergic respiratory diseases. Although the existing intranasal corticosteroids are already highly efficient, the introduction of further improved formulations with a better efficacy/safety profile is always desired. Fluticasone furoate nasal spray is a new topical corticosteroid, with enhanced-affinity and a unique side-actuated delivery device. As it has high topical potency and low potential for systemic effects, it is a good candidate for rhinitis treatment [1].

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After single- and multiple-dose intranasal administration, plasma fluticasone furoate concentrations are below the lower limit of quantification in most patients (Allen et al 2007; Hughes et al 2007; Martin 2007). One study showed that only 2% of samples from patients receiving 110 μg of FF had quantifiable plasma drug concentrations (Martin 2007).
Systemic bioavailability is determined by the sum of 2 components, including the portion of the drug that is absorbed via the nasal mucosa plus the portion that is swallowed. The last one is the major route for circulation, what makes the first-pass hepatic metabolism after drug absorption in the gastrointestinal tract very important[1].

Absorption, Distribution and Excretion
Plasma concentrations of fluticasone furoate may not predict its therapeutic effect. Peak plasma concentrations are reached within 0.5 to 1 hour. When administered by inhalation, the absolute bioavailability of fluticasone furoate is 13.9%, primarily due to partial absorption of the inhaled dose upon reaching the lungs. Oral bioavailability is lower (approximately 1.3%) due to extensive first-pass metabolism. The systemic exposure (AUC) in asthmatic patients is 26% lower than in healthy subjects. Steady-state is reached within 6 days after repeated inhalation of fluticasone furoate, with a drug accumulation up to 2.6 times. Intranasal administration of fluticasone furoate results in patients swallowing a larger dose. Following intravenous administration of radiolabeled fluticasone furoate, mass balance shows that 90% of the radiolabeled substance is present in feces and 2% in urine. After oral administration, 101% of the total dose of radiolabeled substance is recovered in feces, and approximately 1% in urine.
The steady-state mean volume of distribution after intravenous administration in healthy subjects was 661 liters. A study of 24 healthy Caucasian men showed a steady-state volume of distribution of 704 liters after intravenous administration.
After intravenous administration in healthy subjects, fluticasone furoate is primarily cleared from systemic circulation via hepatic CYP3A4 metabolism, with a total plasma clearance of 65.4 L/h. A study of 24 healthy Caucasian men also showed a clearance of 71.8 L/h after intravenous administration.

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Metabolism/Metabolites
Fluticasone furoate is primarily cleared from systemic circulation via hepatic CYP3A4 metabolism, generating metabolites with significantly reduced corticosteroid activity. No evidence was found of partial cleavage of furoate esters to generate fluticasone in vivo. Fluticasone furoate is also hydrolyzed at the 5-S-fluoromethylthiocarbamate group to generate an inactive metabolite.

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Biological Half-Life
The mean plasma elimination half-life after repeated inhalation administration is 24 hours. A study of 24 healthy white men showed that the half-life after intravenous administration was 13.6 hours and the half-life after inhalation was 17.3–23.9 hours. After single and multiple intranasal administrations, plasma concentrations of fluticasone furoate were generally below the lower limit of quantitation in most patients. [1] The mean absolute bioavailability after intranasal administration (880 µg every 8 hours for 10 times) in healthy volunteers was 0.5%. [1] The oral bioavailability after a single oral 2 mg dose was 1.26%. [1] The elimination half-life after a single intravenous administration was 15.1 hours. [1] In vitro studies have shown that fluticasone furoate is 99.4% bound to plasma proteins. [1]
This drug undergoes extensive first-pass metabolism in the liver via the cytochrome P450 isoenzyme CYP3A4, which hydrolyzes it into a 17β-carboxylic acid metabolite (M10), which has low glucocorticoid receptor agonist potency. [1]
Fluticasone furoate is mainly excreted in feces, with only a small amount appearing in urine. [1]

Protein Binding
Fluticasone furoate has a protein binding rate of >99% in serum, with a maximum of 99.6%, primarily binding to albumin (96%) and α1-acid glycoprotein (90%). In a pooled analysis of clinical trials, the overall incidence of adverse events with intranasal fluticasone furoate was similar to that with placebo. [1] The most common adverse events (≥1% in adolescents/adults or ≥3% in children, and higher than placebo) included headache, epistaxis, nasopharyngitis, fever, sore throat, nasal ulcers, cough, and back pain. [1] Epistaxis was the only more frequent and severe adverse event in patients receiving fluticasone furoate compared to placebo, especially during long-term (12 months) treatment. [1]
Caution should be exercised when using this medication in combination with potent CYP3A4 inhibitors (such as ketoconazole and ritonavir), as this may increase the systemic exposure to fluticasone furoate and potentially increase the risk of systemic adverse reactions. [1]

[1]. Fluticasone furoate nasal spray in the treatment of allergic rhinitis. Ther Clin Risk Manag. 2008 Apr;4(2):465-72.

[2]. Asthma phenotypes and T-bet protein expression in cells treated with Fluticasone Furoate/Vilanterol. Pulm Pharmacol Ther. 2020 Feb;60:101886.

Fluticasone furoate is a trifluorinated corticosteroid with the structure 6α,9-difluoro-11β,17α-dihydroxy-17β-{[(fluoromethyl)thio]carbonyl}-16-methyl-3-oxoandrost-1,4-diene, with a 2-furanyl substituent at position 17. It is used in combination with vilanterol tribenzoate to treat bronchospasm associated with chronic obstructive pulmonary disease. It has dual effects as an anti-allergic, prodrug, and anti-asthmatic agent. It is an 11β-hydroxy steroid, corticosteroid, fluorinated steroid, steroid ester, 2-furanate, thioester, and 3-oxo-Δ(1),Δ(4)-steroid. Its function is related to fluticasone. It is derived from the hydride of androstane. Fluticasone furoate is a synthetic glucocorticoid available in inhaler and nasal spray formulations for the treatment of various inflammatory diseases. Fluticasone furoate was first approved for marketing in 2007. Fluticasone furoate is the furoate form of fluticasone, a synthetic trifluorinated glucocorticoid receptor agonist with anti-allergic, anti-inflammatory, and antipruritic effects. After administration, fluticasone binds to and activates the glucocorticoid receptor, thereby activating lipocortin. Lipocorticoid, in turn, inhibits cytosolic phospholipase A2 and a series of reactions involved in the synthesis of inflammatory mediators such as prostaglandins and leukotrienes. Secondly, mitogen-activated protein kinase (MAPK) phosphatase 1 is induced, leading to dephosphorylation and inactivation of the Jun N-terminal kinase, directly inhibiting c-Jun-mediated transcription. Finally, the transcriptional activity of nuclear factor (NF)-κB is blocked, thereby inhibiting the transcription of cyclooxygenase 2 (COX-2), which is crucial for prostaglandin production. See also: Fluticasone (contains the active ingredient); Fluticasone furoate; Vilanterol benzoate (ingredient)... See more...

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Drug Indications
Fluticasone furoate is indicated for once-daily maintenance (i.e., preventative) treatment of asthma in patients aged 5 years and older. Fluticasone furoate is available in two combination formulations—one in combination with vilanterol, and the other in combination with vilanterol and umemet—both indicated for the treatment of chronic obstructive pulmonary disease (COPD) and asthma. The vilanterol-umemet-fluticasone furoate combination is indicated for patients aged 18 years and older, and the vilanterol-fluticasone furoate combination is indicated for patients aged 5 years and older. Fluticasone furoate nasal spray is available without a prescription for the treatment of hay fever and other upper respiratory tract allergy symptoms in patients aged 2 years and older.
FDA Label
Adults, adolescents (12 years and older), and children (6–11 years). Avamys is indicated for the treatment of symptoms of allergic rhinitis. Adults, adolescents (12 years and older), and children (6-11 years). Alisade is indicated for the treatment of symptoms of allergic rhinitis. Mechanism of Action: In vitro studies have shown that fluticasone furoate has a binding affinity to human glucocorticoid receptors approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. The clinical significance of these findings is unclear. The exact mechanism by which fluticasone furoate affects asthma symptoms is unknown. Inflammation is an important component of the pathogenesis of asthma. Studies have shown that corticosteroids have broad effects on various cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and inflammatory mediators (e.g., histamine, arachidic acid, leukotrienes, cytokines). In vitro and in vivo models have confirmed the following specific effects of fluticasone furoate: activation of glucocorticoid response elements, inhibition of pro-inflammatory transcription factors such as NF-κB, and inhibition of antigen-induced eosinophilia in sensitized rats. The anti-inflammatory effects of these corticosteroids may contribute to their efficacy. Fluticasone furoate is a synthetic trifluorinated topical glucocorticoid with enhanced receptor affinity and potent anti-inflammatory activity. [1] It is formulated as an aqueous nasal spray for topical administration to the nasal mucosa. Each spray releases 27.5 µg of fluticasone furoate in a volume of 50 µL. [1] This formulation contains excipients/preservatives including benzalkonium chloride (0.015% w/w), anhydrous glucose, disodium edetate, microcrystalline cellulose, sodium carboxymethyl cellulose, polysorbate 80, and purified water. [1] This product is administered via a unique side-spray nasal spray designed to minimize dose variability and throat secretions. [1] The recommended starting dose is 55 µg once daily for children and 110 µg once daily for adults and adolescents. [1]
This product is indicated for the treatment of allergic rhinitis symptoms in patients aged 2 years and older. [1]
This product works by binding to intracellular glucocorticoid receptors, thereby inhibiting the production of various cytokines, chemokines, enzymes, and cell adhesion molecules involved in inflammation. [1]
Its low systemic bioavailability and high plasma protein binding rate result in minimal systemic adverse reactions. [1]

C27H29O6F3S

538.57576

538.163

C, 60.21; H, 5.43; F, 10.58; O, 17.82; S, 5.95

397864-44-7

Fluticasone (propionate);80474-14-2;Fluticasone furoate-d3

9854489

White to off-white solid powder

1.4±0.1 g/cm3

625.2±55.0 °C at 760 mmHg

250-252

331.9±31.5 °C

0.0±1.9 mmHg at 25°C

1.584

4.01

1

10

6

37

1080

9

C[C@@H]1C[C@H]2[C@@H]3C[C@@H](C4=CC(=O)C=C[C@]4(C)[C@]3([C@H](C[C@]2(C)[C@]1(C(=O)SCF)OC(=O)C5=CC=CO5)O)F)F

XTULMSXFIHGYFS-VLSRWLAYSA-N

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

(6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-17-(((fluoromethyl)thio)carbonyl)-11-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl furan-2-carboxylate

Avamys; Veramyst; Fluticasone furoate; 397864-44-7; Veramyst; Avamys; Allermist; Furamist; Arnuity Ellipta; Alisade; Allermist

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)

DMSO : ~100 mg/mL (~185.67 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.64 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 25.0 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: ≥ 2.5 mg/mL (4.64 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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