The primary target of Flunisolide is the glucocorticoid receptor (GR), a member of the nuclear receptor superfamily. Flunisolide acts as a glucocorticoid receptor agonist, binding to the receptor with high affinity. This binding induces a conformational change that promotes the translocation of the receptor from the cytoplasm to the nucleus. In the nucleus, the GR complex binds to glucocorticoid response elements (GREs) in the DNA, leading to the transactivation of anti-inflammatory genes and the transrepression of pro-inflammatory genes. This mechanism underlies the compound's potent anti-inflammatory and immunosuppressive activities.

Lung fibroblasts that have been isolated from the lung are prevented from activating by flunisolide (0.1–10 μM, 1 hour) [1]. Flunisolide (10 μM, 24 hours) causes sputum eosinophils to undergo apoptosis and decreases the release of MMP-9, TIMP-1, TGF-β, and fibronectin from sputum cells isolated from individuals with mild to moderate asthma [2]. In BEAS-2B cells, flunisolide (0.1–10 µM µM, 24 hours) efficiently suppresses TNF-α-induced ICAM-1 expression as well as GM-CSF and IL-5 production [3]. It has been demonstrated that flunisolide (115 µM, 0–3 hours) is ATP-dependent and can move polarizedly in Calu-3 cells from the apical (ap) to the basolateral (bl) direction [4].

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In vitro, Flunisolide exhibits potent glucocorticoid receptor agonist activity. It induces eosinophil apoptosis, which is a key mechanism for its anti-inflammatory effect in allergic diseases. The compound's activity is assessed in cell-based assays that measure glucocorticoid receptor activation, such as reporter gene assays or assays measuring the expression of glucocorticoid-responsive genes. However, detailed IC50 or EC50 values for Flunisolide are not extensively reported in the available literature.

In silicosis mice, flunisolide (intranasal treatment, 0.3–10 µg/mouse, daily, commencing on days 21–27) enhances the rate of silicon particle clearance in the lungs while simultaneously inhibiting lung inflammation, fibrosis, and airway hyperresponsiveness [1]. The intranasal administration of flunisolide (0.3–10 µg/mouse, daily, days 21–27) prevents the formation of macrophages and myofibroblasts in lung tissue caused by silica [1].

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In vivo, Flunisolide demonstrates potent anti-inflammatory activity. It is effective in the treatment of allergic rhinitis and asthma when administered via the intranasal or inhaled route. The compound's in vivo efficacy is attributed to its ability to activate the glucocorticoid receptor and suppress the inflammatory response. It reduces the symptoms of allergic rhinitis, including nasal congestion, rhinorrhea, and sneezing, and improves lung function in asthma patients.

In vitro receptor binding assays for Flunisolide typically involve measuring its binding affinity to the glucocorticoid receptor. The receptor is incubated with a radiolabeled glucocorticoid ligand (e.g., [³H]-dexamethasone) in the presence of varying concentrations of Flunisolide. After incubation to reach equilibrium, bound and free ligands are separated, and the radioactivity is measured. The compound's affinity is expressed as the IC50 or Ki for displacement of the radiolabeled ligand.

Apoptosis analysis [2]
Cell Types: eosinophils
Tested Concentrations: 10 μM
Incubation Duration: 24 h
Experimental Results: Induced apoptosis of sputum eosinophils.

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Cellular assays for Flunisolide are performed using glucocorticoid-responsive cell lines. Cells are treated with Flunisolide, and the expression of glucocorticoid-responsive genes is measured by quantitative PCR or reporter gene assays. The compound's ability to induce eosinophil apoptosis is assessed by flow cytometry or by measuring caspase activity. These assays are used to study the cellular pharmacology of Flunisolide and to compare its activity with other glucocorticoids.

Animal/Disease Models: Male Swiss-Wechsler mouse (intranasal instillation, crystalline silica, 10 mg/50 µL, particle size 0.5-10 µm) [1]
Doses: 0.3-10 µg/mouse daily, day 21 -27-day intranasal administration
Experimental Results: diminished granulomatous reactions, collagen deposition associated with granuloma formation induced by silica particles. Reduce the number of F4/80 and α-SMA positive cells.

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In vivo animal studies with Flunisolide are typically performed in models of allergic inflammation. For example, in a murine model of allergic rhinitis, animals are sensitized to an allergen and then challenged intranasally. Flunisolide is administered intranasally, and the reduction in inflammatory cell infiltration, mucus production, and cytokine levels is measured. In models of asthma, Flunisolide is administered via inhalation, and its effects on airway hyperresponsiveness and inflammation are assessed.

Absorption, Distribution and Excretion
Absorption is rapid. Metabolism/Metabolites Primarily metabolized in the liver, converted into Sβ-OH metabolites. Biological Half-Life 1.8 hours

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Flunisolide is administered via the intranasal or inhaled route for the treatment of allergic rhinitis and asthma. When administered intranasally, it has a rapid onset of action and is well-tolerated. The compound undergoes extensive first-pass metabolism in the liver, and its systemic bioavailability is low, which minimizes the risk of systemic side effects. However, detailed pharmacokinetic parameters such as half-life, clearance, and volume of distribution are not extensively reported in the available literature.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Although measurements have not been performed, the amount of inhaled corticosteroids absorbed into the mother's bloodstream and secreted into breast milk is likely too small to affect breastfed infants. Expert opinion is that inhaled, nasal, and oral corticosteroids are safe to use during lactation.
◉ Effects on Breastfed Infants
Currently, there are no reports of any effects of corticosteroids on breastfed infants.
◉ Effects on Lactation and Breast Milk
As of the revision date, no relevant published information was found.

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Protein Binding Rate
Approximately 40% after oral inhalation.

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Flunisolide is generally well-tolerated when administered at therapeutic doses. Common side effects include nasal irritation, dryness, and epistaxis. Systemic side effects, such as adrenal suppression, are rare due to the low systemic bioavailability of the compound. However, long-term use of corticosteroids can be associated with various adverse effects, including osteoporosis, glaucoma, and immunosuppression. Comprehensive toxicology data for Flunisolide are available from its clinical use and regulatory filings.

[1]. Intranasal Flunisolide Suppresses Pathological Alterations Caused by Silica Particles in the Lungs of Mice. Front Endocrinol (Lausanne). 2020 Jun 17;11:388.

[2]. In vitro effects of flunisolide on MMP-9, TIMP-1, fibronectin, TGF-beta1 release and apoptosis in sputum cells freshly isolated from mild to moderate asthmatics. Allergy. 2004 Sep;59(9):927-32.

[3]. Modulation by flunisolide of tumor necrosis factor-alpha-induced stimulation of airway epithelial cell activities related to eosinophil inflammation. J Asthma. 2010 May;47(4):381-7.

[4]. Evidence of P-glycoprotein mediated apical to basolateral transport of flunisolide in human broncho-tracheal epithelial cells (Calu-3). Br J Pharmacol. 2001 Dec;134(7):1555-63.

According to state or federal labeling requirements, flunisolone may cause developmental toxicity and female reproductive toxicity. Flunisolone is a fluorinated steroid, cyclic ketal, 20-oxosteroid, 21-hydroxysteroid, 11β-hydroxysteroid, 3-oxo-Δ(1),Δ(4)steroid, and primary α-hydroxyketone. It has immunosuppressant, anti-inflammatory, and anti-asthmatic effects. Flunisolone (trade names: AeroBid, Nasalide, Nasarel) is a corticosteroid with anti-inflammatory effects. It is commonly used to treat allergic rhinitis, and its main mechanism of action is activation of glucocorticoid receptors. Anhydrous flunisolone is a corticosteroid. The mechanism of action of anhydrous flunisolone is as a corticosteroid hormone receptor agonist. Flunisolone is a synthetic corticosteroid with anti-inflammatory and anti-allergic properties. Flunisolone is a glucocorticoid receptor agonist that binds to cytoplasmic glucocorticoid receptors, then translocates to the nucleus, initiating the transcription of glucocorticoid-responsive genes (such as lipocortin). Lipocorticoids inhibit phospholipase A2, thereby blocking the release of arachidonic acid from membrane phospholipids and inhibiting the synthesis of prostaglandins and leukotrienes, both potent inflammatory mediators. Drug Indications For maintenance and prophylactic treatment of asthma. FDA Label Mechanism of Action Flunisolone is a glucocorticoid receptor agonist. The anti-inflammatory effects of corticosteroids are thought to be related to lipocortin, a phospholipase A2 inhibitory protein that controls the biosynthesis of prostaglandins and leukotrienes by inhibiting arachidonic acid. Corticosteroids suppress the immune system by reducing lymphatic function, decreasing immunoglobulin and complement concentrations, inducing lymphopenia, and interfering with antigen-antibody binding. Flunisolone binds to the plasma cortisol transporter and is active only when it is no longer bound to the cortisol transporter.

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Pharmacodynamics
Flunisolone is a synthetic corticosteroid. It is used in the form of a metered-dose inhaler to treat asthma, or in the form of a nasal spray to treat allergic rhinitis. Corticosteroids are naturally occurring hormones that can prevent or suppress inflammatory and immune responses. When used as a nasal spray, flunisolone can reduce common allergy symptoms such as runny nose, nasal congestion, postnasal drip, sneezing, and itching at the back of the throat.

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Flunisolide is an FDA-approved corticosteroid medication for the treatment of allergic rhinitis and asthma. It is available as a nasal spray (Nasalide, Nasarel) and as an inhalation aerosol (AeroBid). The compound's anti-inflammatory activity is mediated through the activation of the glucocorticoid receptor. It is effective in reducing the symptoms of allergic rhinitis and improving lung function in asthma. Flunisolide is generally well-tolerated and has a favorable safety profile.

C24H31FO6

434.4977

434.21

3385-03-3

Flunisolide hemihydrate;77326-96-6;Flunisolide-d6

82153

White to off-white solid powder

1.33g/cm3

581.8ºC at 760mmHg

226-230 ; 245 °C

305.7ºC

2.274

2

7

2

31

910

9

C[C@]12C[C@@H]([C@H]3[C@H]([C@@H]1C[C@@H]4[C@]2(OC(O4)(C)C)C(=O)CO)C[C@@H](C5=CC(=O)C=C[C@]35C)F)O

XSFJVAJPIHIPKU-XWCQMRHXSA-N

InChI=1S/C24H31FO6/c1-21(2)30-19-9-14-13-8-16(25)15-7-12(27)5-6-22(15,3)20(13)17(28)10-23(14,4)24(19,31-21)18(29)11-26/h5-7,13-14,16-17,19-20,26,28H,8-11H2,1-4H3/t13-,14-,16-,17-,19+,20+,22-,23-,24+/m0/s1

(1S,2S,4R,8S,9S,11S,12S,13R,19S)-19-fluoro-11-hydroxy-8-(2-hydroxyacetyl)-6,6,9,13-tetramethyl-5,7-dioxapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one

NasarelFlunisolideBronalideLunisAeroBidNasalideSynaclyn

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 : ~125 mg/mL (~287.69 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.79 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 20.8 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: ≥ 2.08 mg/mL (4.79 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (4.79 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 20.8 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.)