Glucocorticoid receptor

Fluticasone propionate suppresses TNFα-induced E-selectin expression with an IC50 of 1 nM[1].

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Fluticasone propionate is a new corticosteroid based on the androstane nucleus. It is more lipophilic than beclomethasone dipropionate (BDP) and budesonide, and binds more avidly to human lung tissue. It has an absolute affinity (KD) of 0.5 nM for the glucocorticoid receptor and a relative receptor affinity 1.5- and 3.0-times greater than that of beclomethasone-17-monopropionate (17-BMP) and budesonide, respectively. The rate of association with the receptor is faster and the rate of dissociation slower than with standard corticosteroids. As a result, the half-life of the corticosteroid-receptor complex is > 10 h. Fluticasone propionate is also highly selective for the glucocorticoid receptor, with little or no activity at other steroid receptors. Pretreatment with fluticasone propionate significantly inhibits the increase in mast cell numbers in the nasal mucosa of rats chronically exposed to toluene di-isocyanate (TDI), and suppresses TDI-induced mast cell degranulation. It is more potent in vitro than dexamethasone, BDP and budesonide in inhibiting anti-CD3-induced human T-lymphocyte proliferation, in attenuating tumour necrosis factor-alpha-induced endothelial cell adhesion molecule expression, and in increasing secretory leucocyte protease inhibitor levels in airway epithelial cells. It is also more potent and longer-acting than other corticosteroids in inhibiting oedema formation, interleukin-5 (IL-5)-induced blood eosinophilia, and IL-5- or platelet activating factor-stimulated eosinophil accumulation in the lung. Fluticasone propionate therefore has increased intrinsic glucocorticoid potency and high topical anti-inflammatory activity. [2]

fluticasone treatment suppresses rhinovirus-induced airways inflammation in vivo but also impairs anti-viral immune responses and increases viral titres, leading to mucus hypersecretion. Since asthma and chronic obstructive pulmonary disease are both associated with inherent deficient IFN responses to rhinovirus, inhaled corticosteroids might interact synergistically with disease to inhibit IFN and thus lead to increased severity of exacerbation. The clinical applicability of these findings requires confirmation in human models of disease.[3]
At 24 h post infection, fluticasone treatment suppressed rhinovirus induction of type I and III IFNs in the airways (for the fluticasone-treated group compared with controls: mean IFNβ BAL protein 20·2 pg/mL [SD 16·7] vs 103·0 [30·9]; mean IFNλ BAL protein 102·6 pg/mL [17·4] vs 217 [44·6], p<0·001); it also impaired viral clearance, with increased lung tissue viral RNA copy numbers (4·7 × 10(5) copies [SD 1·3] vs 2·6 × 10(5) [0·8], p<0·001). Despite increasing viral loads, fluticasone inhibited rhinovirus-induced airway inflammation as evidenced by suppressed BAL neutrophil numbers in fluticasone compared with control mice (0·021 × 10(5) [0·012] vs 0·59 × (5) [0·39], p<0·001) and by suppressed lymphocyte numbers (0·092 × 10(5) [0·044] vs 0·45 × 10(5) [0·11], p<0·001). By contrast, fluticasone increased MUC5AC proteins (158·2 arbitrary units [29·9] vs 107·6 [7·1], p=0·0165) and MUC5B proteins (623·8 arbitrary units [231·9] vs 413·5 [70·5], p=0·0476) in BAL at day 7 post infection. Administration of intranasal recombinant IFN beta (10(4) units) with fluticasone and rhinovirus 1B led to upregulation of interferon-inducible cytokines OAS and CXCL10/IP-10 compared with control mice treated with fluticasone and rhinovirus alone and improved viral clearance without having any effect on suppression of inflammation by fluticasone.[3]
Fluticasone propionate administrated after induction of a severe heaves exacerbation results in complete resolution of clinical signs, normalization of pulmonary function tests, and significant decrease in bronchoalveolar lavage (BAL) neutrophilia in horse.

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Fluticasone propionate is a potent topical anti-inflammatory corticosteroid with low systemic activity. Available pharmacodynamic data are only preliminary; however, large placebo- and drug-controlled clinical studies involving almost 4000 patients with seasonal allergic rhinitis and 1500 with perennial allergic and nonallergic rhinitis have confirmed the efficacy of intranasal fluticasone propionate in the control of nasal symptoms. Fluticasone propionate generally demonstrated similar efficacy compared with intranasal beclomethasone dipropionate, flunisolide acetonide and oral astemizole and better or a trend towards better efficacy compared with oral loratadine, terfenadine, cetirizine and intranasal sodium cromoglycate (cromolyn sodium) against nasal symptoms. The incidence of adverse effects in association with intranasal fluticasone propionate appears to be comparable to that observed with placebo; the most frequently reported effects are nasal dryness/burning, epistaxis and headache. Consistent with its minimal systemic availability, intranasal fluticasone propionate in a dosage of up to 4 mg/day does not cause adrenal suppression. Thus, based on early data from large clinical trials, fluticasone propionate administered once daily offers an effective and convenient treatment option in patients with seasonal and perennial allergic rhinitis, and is distinguished by its low oral bioavailability. [1]

Fluticasone propionate is a new corticosteroid based on the androstane nucleus. It is more lipophilic than beclomethasone dipropionate (BDP) and budesonide, and binds more avidly to human lung tissue. It has an absolute affinity (KD) of 0.5 nM for the glucocorticoid receptor and a relative receptor affinity 1.5- and 3.0-times greater than that of beclomethasone-17-monopropionate (17-BMP) and budesonide, respectively. The rate of association with the receptor is faster and the rate of dissociation slower than with standard corticosteroids. As a result, the half-life of the corticosteroid-receptor complex is > 10 h. Fluticasone propionate is also highly selective for the glucocorticoid receptor, with little or no activity at other steroid receptors. Pretreatment with fluticasone propionate significantly inhibits the increase in mast cell numbers in the nasal mucosa of rats chronically exposed to toluene di-isocyanate (TDI), and suppresses TDI-induced mast cell degranulation. It is more potent in vitro than dexamethasone, BDP and budesonide in inhibiting anti-CD3-induced human T-lymphocyte proliferation, in attenuating tumour necrosis factor-alpha-induced endothelial cell adhesion molecule expression, and in increasing secretory leucocyte protease inhibitor levels in airway epithelial cells. It is also more potent and longer-acting than other corticosteroids in inhibiting oedema formation, interleukin-5 (IL-5)-induced blood eosinophilia, and IL-5- or platelet activating factor-stimulated eosinophil accumulation in the lung. Fluticasone propionate therefore has increased intrinsic glucocorticoid potency and high topical anti-inflammatory activity [2].

C57BL/6 mice were intranasally dosed with fluticasone propionate (1 mg/kg) or vehicle (dimethyl sulfoxide, control), 1 h before infection with rhinovirus 1B. We assessed bronchoalveolar lavage (BAL) inflammatory cell numbers, and measured gene expression, protein production of innate mediators, or both by quantitative RT-PCR or ELISA. We compared mice treated with fluticasone with controls at various timepoints after infection. In additional experiments, recombinant interferon (IFN) beta was administered with fluticasone and rhinovirus 1B in both groups of mice[3].

Absorption, Distribution and Excretion
The intranasal bioavailability of fluticasone propionate is <2%, and the oral bioavailability is <1%. After intranasal administration, most of the dose is swallowed. Local absorption of fluticasone propionate is low but can be affected by various factors, including skin integrity and the presence of inflammation or disease. A study of 24 healthy Caucasian men showed an inhaled bioavailability of 9.0%. Fluticasone propionate is primarily excreted in feces, with urinary excretion <5%. The intravenous volume of distribution of fluticasone propionate is 4.2 L/kg. A study of 24 healthy Caucasian men showed a steady-state volume of distribution of 577 L after intravenous administration. The blood flow rate of fluticasone propionate is 1093 mL/min. A study of 24 healthy Caucasian men showed a clearance rate of 63.9 L/h after intravenous administration.

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Metabolism/Metabolites
Fluticasone propionate is primarily metabolized and cleared by the liver via cytochrome P450 3A4. Fluticasone propionate is hydrolyzed at the 5-S-fluoromethyl thiocarbamate group to produce an inactive metabolite.

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Biological Half-Life
The half-life of intravenously administered fluticasone propionate is 7.8 hours. A study of 24 healthy Caucasian men showed a half-life of 14.0 hours after intravenous administration and 10.8 hours after inhalation.

Protein Binding
Fluticasone propionate showed a 99% protein binding rate in serum. However, the protein binding rate of fluticasone propionate in serum was only 91% when applied topically.

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444036 Oral LD50 in rats >2 gm/kg Yakuri to Chiryo. Pharmacology and Therapeutics., 20(1493), 1992
444036 Inhalation LC in rats >40770 ug/m3/1 Heart: Changes in heart weight Yakuri to Chiryo. Pharmacology and Therapeutics., 20(1501), 1992
444036 Subcutaneous LD50 in rats >1 gm/kg Endocrine: Other changes; Blood: Changes in serum components (EG, TP, bilirubin, cholesterol) Pharmacology and Therapeutics, 20(1493), 1992

[1]. Intranasal fluticasone propionate. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in allergic rhinitis. Drugs. 1992;43(5):760-775.

[2]. Johnson M. The anti-inflammatory profile of fluticasone propionate. Allergy. 1995;50(23 Suppl):11-14.

[3]. Effect of fluticasone propionate on virus-induced airways inflammation and anti-viral immune responses in mice. Lancet. 2015 Feb 26;385 Suppl 1:S88.

Fluticasone propionate may cause developmental toxicity depending on state or federal labeling requirements. Fluticasone propionate 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 propionyl substituent at position 17; it possesses anti-inflammatory, anti-asthmatic, and anti-allergic activities. It can be used as an anti-allergy drug, anti-asthmatic drug, anti-inflammatory drug, dermatological drug, bronchodilator, and adrenergic agonist. It is a corticosteroid, steroid ester, 11β-hydroxysteroid, propionate ester, fluorinated steroid, thioester, and 3-oxo-Δ(1),Δ(4) steroid. Its function is related to fluticasone. It is derived from the hydride of androstane. Fluticasone propionate is a synthetic glucocorticoid. These medications are available in inhaler, nasal spray, and topical formulations for the treatment of various inflammatory diseases. Fluticasone propionate was first approved in 1990. Fluticasone propionate is the propionate form of fluticasone, a synthetic trifluorinated glucocorticoid receptor agonist with anti-allergic, anti-inflammatory, and antipruritic effects. Binding and activation of glucocorticoid receptors lead to the activation of lipocortin, which in turn inhibits cytosolic phospholipase A2, triggering 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, which is essential for prostaglandin production. Fluticasone propionate is a steroid with glucocorticoid receptor activity used to treat asthma symptoms; allergic rhinitis; and atopic dermatitis. See also: Fluticasone (active ingredient); Fluticasone propionate; Salmeterol/Roxinafolate (ingredient); Azelastine hydrochloride; Fluticasone propionate (ingredient)... See more...

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Drug Indications
Fluticasone propionate inhaler is indicated for the prevention and treatment of asthma and inflammatory and pruritic skin conditions. Fluticasone propionate nasal spray is indicated for the treatment of allergic and non-allergic rhinitis.
FDA Label
Asthma Treatment

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Mechanism of Action
Fluticasone propionate affects various cell types and inflammatory mediators through an unknown mechanism. Fluticasone propionate activates glucocorticoid receptors and inhibits pulmonary eosinophilia in rats.

C25H31F3O5S

500.57

500.184

C, 59.99; H, 6.24; F, 11.39; O, 15.98; S, 6.41

80474-14-2

Fluticasone furoate;397864-44-7;Fluticasone propionate-d5;1093258-28-6;Fluticasone propionate-d3;Fluticasone;90566-53-3

444036

Endogenous Metabolite

White to off-white solid powder

1.3±0.1 g/cm3

568.3±50.0 °C at 760 mmHg

275 °C

297.5±30.1 °C

0.0±3.5 mmHg at 25°C

1.556

3.73

1

9

6

34

984

9

O([C@@]1([C@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(C=C[C@]4(C)[C@]3([C@H](C[C@]12C)O)F)=O)C(=O)SCF)C(=O)CC

WMWTYOKRWGGJOA-CENSZEJFSA-N

InChI=1S/C25H31F3O5S/c1-5-20(31)33-25(21(32)34-12-26)13(2)8-15-16-10-18(27)17-9-14(29)6-7-22(17,3)24(16,28)19(30)11-23(15,25)4/h6-7,9,13,15-16,18-19,30H,5,8,10-12H2,1-4H3/t13-,15+,16+,18+,19+,22+,23+,24+,25+/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 propionate

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.99 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.)