Corticosteroid (Kd = 0.3 nM)

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].

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].

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
Fluticasone furoate plasma levels may not predict therapeutic effect. Peak plasma concentrations are reached within 0.5 to 1 hour. Absolute bioavailability of fluticasone furoate when administrated by inhalation was 13.9%, primarily due to absorption of the inhaled portion of the dose delivered to the lung. Oral bioavailability from the swallowed portion of the dose is low (approximately 1.3%) due to extensive first-pass metabolism. Systemic exposure (AUC) in subjects with asthma was 26% lower than observed in healthy subjects. Following repeat dosing of inhaled fluticasone furoate, steady state was achieved within 6 days with up to 2.6-fold accumulation. Intranasal exposure of fluticasone furoate also results in patients swallowing a larger portion of the dose.
Following intravenous dosing with radiolabeled fluticasone furoate, mass balance showed 90% of radiolabel in the feces and 2% in the urine. Following oral dosing, radiolabel recovered in feces was 101% of the total dose, and that in urine was approximately 1% of the total dose.
Following intravenous administration to healthy subjects, the mean volume of distribution at steady state was 661 L. A study of 24 healthy Caucasian males showed a volume of distribution at steady state of 704L following intravenous administration.
Following intravenous administration to healthy subjects, fluticasone furoate was cleared from systemic circulation principally by hepatic metabolism via CYP3A4 with a total plasma clearance of 65.4 L/hr. A study of 24 healthy Caucasian males also showed a clearance of 71.8L/h following intravenous administration.

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Metabolism / Metabolites
Fluticasone furoate is cleared from systemic circulation principally by hepatic metabolism via CYP3A4 to metabolites with significantly reduced corticosteroid activity. There was no in vivo evidence for cleavage of the furoate moiety resulting in the formation of fluticasone. Fluticasone furoate is also hydrolyzed at the FIVE-S-fluoromethyl carbothioate group, forming an inactive metabolite.

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Biological Half-Life
Following repeat-dose inhaled administration, the plasma elimination phase half-life averaged 24 hours. A study of 24 healthy Caucasian males showed a half-life of 13.6 hours following intravenous administration and 17.3-23.9 hours following inhalation.

Protein Binding
Fluticasone furoate is >99% protein bound in serum and may be as high as 99.6%, predominantly to albumin (96%) and α1-acid glycoprotein (90%).

[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 that consists of 6alpha,9-difluoro-11beta,17alpha-dihydroxy-17beta-{[(fluoromethyl)sulfanyl]carbonyl}-16-methyl-3-oxoandrosta-1,4-diene bearing a 2-furoyl substituent at position 17. Used in combination with vilanterol trifenate for treatment of bronchospasm associated with chronic obstructive pulmonary disease. It has a role as an anti-allergic agent, a prodrug and an anti-asthmatic drug. It is an 11beta-hydroxy steroid, a corticosteroid, a fluorinated steroid, a steroid ester, a 2-furoate ester, a thioester and a 3-oxo-Delta(1),Delta(4)-steroid. It is functionally related to a fluticasone. It derives from a hydride of an androstane.
Fluticasone furoate is a synthetic glucocorticoid available as an inhaler and nasal spray for various inflammatory indications. Fluticasone furoate was first approved in 2007.
Fluticasone Furoate is the furoate salt form of fluticasone, a synthetic trifluorinated glucocorticoid receptor agonist with anti-allergic, anti-inflammatory and anti-pruritic effects. Upon administration, fluticasone binds to and activates glucocorticoid receptor, resulting in the activation of lipocortin. Lipocortin, in turn, inhibits cytosolic phospholipase A2 and the cascade of reactions involved in the synthesis of inflammatory mediators, such as prostaglandins and leukotrienes. Secondly, mitogen-activated protein kinase (MAPK) phosphatase 1 is induced, which leads to dephosphorylation and inactivation of Jun N-terminal kinase and directly inhibits c-Jun mediated transcription. Finally, transcriptional activity of nuclear factor (NF)-kappa-B is blocked, thereby inhibiting the transcription of cyclooxygenase 2 (COX-2), which is essential for prostaglandin production.
See also: Fluticasone (has active moiety); Fluticasone furoate; vilanterol trifenatate (component of) ... View More ...

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Drug Indication
Fluticasone furoate is indicated for once-daily maintenance (i.e. prophylactic) treatment of asthma in patients ≥5 years old. Fluticasone furoate is available in two combination medications - one in combination with [vilanterol] and one in combination with both vilanterol and [umeclidinium]- which are both indicated for the management of chronic obstructive pulmonary disease (COPD) and for the treatment of asthma in patients ≥18 years old for the vilanterol-umeclidinium-fluticasone product and ≥5 years old for the vilanterol-fluticasone product. Fluticasone furoate is available over the counter as a nasal spray for the symptomatic treatment of hay fever and other upper respiratory allergies in patients ≥2 years old.
FDA Label
Adults, adolescents (12 years and over) and children (6-11 years). Avamys is indicated for the treatment of the symptoms of allergic rhinitis.
Adults, adolescents (12 years and over) and children (6 - 11 years). Alisade is indicated for the treatment of the symptoms of allergic rhinitis.

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Mechanism of Action
Fluticasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. The clinical relevance of these findings is unknown. The precise mechanism through which fluticasone furoate affects asthma symptoms is not known. Inflammation is an important component in the pathogenesis of asthma. 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. These anti-inflammatory actions of corticosteroids may contribute to their efficacy.

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.)