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
Intranasal bioavailability of fluticasone propionate is <2%, and oral bioavailability is <1%. Intranasal exposure results in the majority of the dose being swallowed. Topical absorption of fluticasone propionate is very low but can change depending on a number of factors including integrity of the skin and the presence of inflammation or disease. A study of 24 healthy Caucasian males showed an inhaled bioavailability of 9.0%.
Fluticasone propionate is mainly eliminated in the feces with <5% eliminated in the urine.
The volume of distribution of intravenous fluticasone propionate is 4.2L/kg. A study of 24 healthy Caucasian males showed a volume of distribution at steady state of 577L following intravenous administration.
1093mL/min for fluticasone propionate. A study of 24 healthy Caucasian males showed a clearance of 63.9L/h following intravenous administration.

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Metabolism / Metabolites
Fluticasone propionate is cleared from hepatic metabolism by cytochrome P450 3A4. Fluticasone propionate is hydrolysed at the FIVE-S-fluoromethyl carbothioate group, forming an inactive metabolite.

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Biological Half-Life
7.8 hours for intravenous fluticasone propionate. A study of 24 healthy Caucasian males shows a half life of 14.0 hours following intravenous administration and 10.8 hours following inhalation.

Protein Binding
Fluticasone propionate is 99% protein bound in serum. Topical fluticasone propionate is only 91% protein bound in serum however.

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444036 rat LD50 oral >2 gm/kg Yakuri to Chiryo. Pharmacology and Therapeutics., 20(1493), 1992
444036 rat LC inhalation >40770 ug/m3/1 CARDIAC: CHANGES IN HEART WEIGHT Yakuri to Chiryo. Pharmacology and Therapeutics., 20(1501), 1992
444036 rat LD50 subcutaneous >1 gm/kg ENDOCRINE: OTHER CHANGES; BLOOD: CHANGES IN SERUM COMPOSITION (E.G., TP, BILIRUBIN, CHOLESTEROL) Yakuri to Chiryo. 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 can cause developmental toxicity according to state or federal government labeling requirements.
Fluticasone propionate 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 propionyl substituent at position 17; has anti-inflammatory, anti-asthmatic and anti-allergic activity. It has a role as an anti-allergic agent, an anti-asthmatic drug, an anti-inflammatory drug, a dermatologic drug, a bronchodilator agent and an adrenergic agent. It is a corticosteroid, a steroid ester, an 11beta-hydroxy steroid, a propanoate ester, a fluorinated steroid, 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 propionate is a synthetic glucocorticoid. These drugs are available as inhalers, nasal, sprays, and topical treatments for various inflammatory indications. Fluticasone propionate was first approved in 1990.
Fluticasone Propionate is the propionate salt form of fluticasone, a synthetic trifluorinated glucocorticoid receptor agonist with antiallergic, antiinflammatory and antipruritic effects. Binding and activation of the glucocorticoid receptor results in the activation of lipocortin that in turn inhibits cytosolic phospholipase A2, which triggers cascade of reactions involved in synthesis of inflammatory mediators, such as prostaglandins and leukotrienes. Secondly, mitogen-activated protein kinase (MAPK) phosphatase 1 is induced, thereby leads to dephosphorylation and inactivation of Jun N-terminal kinase directly inhibiting c-Jun mediated transcription. Finally, transcriptional activity of nuclear factor (NF)-kappa-B is blocked, thereby inhibits the transcription of cyclooxygenase 2, which is essential for prostaglandin production.
A STEROID with GLUCOCORTICOID RECEPTOR activity that is used to manage the symptoms of ASTHMA; ALLERGIC RHINITIS, and ATOPIC DERMATITIS.
See also: Fluticasone (has active moiety); Fluticasone propionate; salmeterol xinafoate (component of); Azelastine hydrochloride; fluticasone propionate (component of) ... View More ...

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Drug Indication
Fluticasone propionate is indicated as an inhaler for the treatment and management of asthma by prophylaxisas well as inflammatory and pruritic dermatoses. Fluticasone propionate nasal spray is indicated for managing allergic and nonallergic rhinitis.
FDA Label
Treatment of asthma

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Mechanism of Action
Fluticasone propionate works through an unknown mechanism to affect the action of various cell types and mediators of inflammation. Fluticasone propionate activates glucocorticoid receptors and inhibits lung 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.)