Corticosteroid; SMO

Fluticasone (10-1000 nM, 48 hours) decreases HRV-induced mucin formation and is involved in the regulation of SPDEF regulatory genes and extracellular ATP release [3]. Fluticasone (0-10 μM, 2 hours) suppresses the proliferation of U2OS cells with an EC50 value of 99 nM[2].

Fluticasone (1 mg/kg; intranasal instillation; 7 days) decreases rhinovirus-induced airway inflammation in vivo but also inhibits antiviral immune responses and increases viral titers, leading to mucus hypersecretion [4].

Animal/Disease Models: C57BL/6 mice [4]
Doses: 1 mg/kg
Route of Administration: intranasal instillation; 1 hour before infection with rhinovirus 1B; 7 days
Experimental Results: Inhibition of BAL neutrophil numbers and inhibition of rhinovirus-induced airway inflammation.

Absorption, Distribution and Excretion
Intranasal exposure of [DB08906] results in patients swallowing a larger portion of the dose. However, absorption is poor and metabolism is high, therefore there is negligible systemic exposure with a nasal bioavailability of 0.50% and oral bioavialability of 1.26%. Inhaled bioavailability is 13.9%. A study of 24 healthy Caucasian males showed an inhaled bioavailability of 6.3-18.4%. Intranasal bioavailability of [DB00588] is <2%, and oral bioavailability is <1%. Intranasal exposure results in the majority of the dose being swallowed. Topical absorption of [DB00588] 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%.
[DB08906] is eliminated ≥90% in the feces and 1-2% in the urine. [DB00588] is mainly eliminated in the feces with <5% eliminated in the urine.
608L at steady state for intravenous administration of [DB08906]. Other reports suggest the mean volume of distribution at steady state is 661L. A study of 24 healthy Caucasian males showed a volume of distribution at steady state of 704L following intravenous administration. The volume of distribution of intravenous [DB00588] is 4.2L/kg. A study of 24 healthy Caucasian males showed a volume of distribution at steady state of 577L following intravenous administration.
57.8L/h for [DB08906]. A study of 24 healthy Caucasian males showed a clearance of 71.8L/h following intravenous administration. 1093mL/min for [DB00588]. A study of 24 healthy Caucasian males showed a clearance of 63.9L/h following intravenous administration.
Fluticasone propionate is poorly absorbed from the respiratory and GI tracts following nasal inhalation of the drug as an aqueous spray. Based on indirect calculations, intranasal fluticasone propionate has an absolute systemic bioavailability of less than 2%. A major portion of an intranasal dose of corticosteroids is swallowed and undergoes extensive first-pass metabolism in the liver. In patients with allergic rhinitis receiving intranasal fluticasone propionate for 2-3 weeks, plasma concentrations were above the level of detection of the assay (50 pg/mL) only when recommended dosages were exceeded, and in those instances, only in occasional samples at low concentrations.
Limited data from studies in which radiolabeled fluticasone propionate has been administered orally indicate that the drug is poorly absorbed from the GI tract and undergoes rapid first-pass metabolism in the liver. Preliminary data from a dose-ranging study suggests that the amount of unchanged fluticasone propionate in plasma increases with dose following oral administration, but the bioavailability of the radiolabeled drug averaged about 1% or less after oral doses of 1-40 mg.
Following oral administration of 1 or 16 mg of radiolabeled propionylfluticasone in a few healthy individuals, peak plasma radioactivity levels (expressed as fluticasone propionate equivalents) averaging approximately 1.3 or 9.1 ng/mL, respectively, were achieved within 0.5-6 hours. Since no unchanged fluticasone propionate was detected in plasma for up to 6 hours after oral administration of unlabeled fluticasone propionate given on a separate occasion, the plasma radioactivity noted after administration of the radiolabeled drug was presumed to be fluticasone propionate metabolites. It has been suggested that the presence of small amounts (50-170 pg/mL) of fluticasone propionate in plasma from 6-24 hours after the dose in these individuals potentially may represent rectal reabsorption of unmetabolized drug.
The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle and the integrity of the epidermal barrier. Occlusive dressing enhances penetration. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption.
For more Absorption, Distribution and Excretion (Complete) data for Fluticasone (14 total), please visit the HSDB record page.

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Metabolism / Metabolites
[DB08906] and [DB00588] are cleared from hepatic metabolism by cytochrome P450 3A4. Both are hydrolysed at the FIVE-S-fluoromethyl carbothioate group, forming an inactive metabolite.
Fluticasone propionate is rapidly metabolized in the liver by the cytochrome P-450 isoenzyme CYP3A4; the principal metabolite is the inactive 17beta-carboxylic acid derivative. ... Of the total radioactivity recovered in urine, 18% represented the inactive 17beta-carboxylic acid derivative of fluticasone propionate, 12% represented a less polar metabolite, and the remainder represented more polar metabolites. ... The 17beta-carboxylic acid metabolite of fluticasone propionate accounted for 3-40% of fecal excretion.
The inactive /17beta-carboxylic acid derivative/ had less affinity (approximately 1/2,000) than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man.
No metabolites of fluticasone propionate were detected in an in vitro study of radiolabeled fluticasone propionate incubated in a human skin homogenate.

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Biological Half-Life
15.1 hours for intranasal [DB08906] and 24 hours for the inhaled formulation. A study of 24 healthy Caucasian males showed a half life of 13.6 hours following intravenous administration and 17.3-23.9 hours followed inhalation. 7.8 hours for intravenous [DB00588]. A study of 24 healthy Caucasian males shows a half life of 14.0 hours following intravenous administration and 10.8 hours following inhalation.
Following intravenous dose of 1 mg in healthy volunteers, fluticasone propionate showed polyexponential kinetics and had an average terminal half-life of 7.2 hours (range, 3.2 to 11.2 hours).
The apparent elimination half-life of fluticasone propionate after iv administration is approximately 3 hours.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Topical fluticasone has not been studied during breastfeeding. Since only extensive application of the most potent corticosteroids may cause systemic effects in the mother, it is unlikely that short-term application of topical corticosteroids would pose a risk to the breastfed infant by passage into breastmilk. However, it would be prudent to use the least potent drug on the smallest area of skin possible. It is particularly important to ensure that the infant's skin does not come into direct contact with the areas of skin that have been treated. Current guidelines allow topical corticosteroids to be applied to the nipples just after nursing for eczema, with the nipples cleaned gently before nursing. Only water-miscible cream or gel products should be applied to the breast because ointments may expose the infant to high levels of mineral paraffins via licking.
◉ Effects in Breastfed Infants
Topical application of a corticosteroid with relatively high mineralocorticoid activity (isofluprednone acetate) to the mother's nipples resulted in prolonged QT interval, cushingoid appearance, severe hypertension, decreased growth and electrolyte abnormalities in her 2-month-old breastfed infant. The mother had used the cream since birth for painful nipples.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.
◉ Summary of Use during Lactation
Although not measured, the amounts of inhaled corticosteroids absorbed into the maternal bloodstream and excreted into breastmilk are probably too small to affect a breastfed infant. Expert opinion considers inhaled, nasal and oral corticosteroids acceptable to use during breastfeeding. See also Fluticasone, Topical.
◉ Effects in Breastfed Infants
None reported with any corticosteroid.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
[DB08906] is >99% protein bound in serum and may be as high as 99.6%. [DB00588] is 99% protein bound in serum. Topical [DB00588] is only 91% protein bound in serum however.

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Interactions
A drug interaction study in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations.
In a placebo-controlled crossover study in 8 healthy volunteers, coadministration of a single dose of orally inhaled fluticasone propionate with multiple doses of ketoconazole to steady state resulted in increased plasma fluticasone propionate exposure, a reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol. Caution should be exercised when fluticasone propionate is coadministered with ketoconazole and other known potent cytochrome P450 3A4 inhibitors.

[1]. Thiazolidinediones inhibit airway smooth muscle release of the chemokine CXCL10: in vitro comparison with current asthma therapies. Respir Res. 2012 Oct 4. 13(1):90.

[2]. Identification of select glucocorticoids as Smoothened agonists: potential utility for regenerative medicine. Proc Natl Acad Sci U S A. 2010 May 18. 107(20):9323-8.

[3]. Tiotropium and Fluticasone Inhibit Rhinovirus-Induced Mucin Production via Multiple Mechanisms in Differentiated Airway Epithelial Cells. Front. Cell. Infect. Microbiol., 2020 Jun.

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

Therapeutic Uses
Androstadienes
Fluticasone propionate nasal spray is indicated for the management of the nasal symptoms of seasonal and perennial allergic and nonallergic rhinitis in adults and pediatric patients 4 years of age and older. /Included in US product label/
Fluticasone propionate cream is a medium potency corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. Fluticasone propionate cream may be used with caution in pediatric patients 3 months of age or older. The safety and efficacy of drug use for longer than 4 weeks in this population have not been established. /Included in US product label/
Fluticasone propionate ointment is a medium potency corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses in adult patients. /Included in US product label/
For more Therapeutic Uses (Complete) data for Fluticasone (6 total), please visit the HSDB record page.

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Drug Warnings
Intranasal fluticasone propionate generally is well tolerated. Adverse effects with intranasal fluticasone propionate therapy usually are mild and local and resolve without specific treatment. The manufacturer states that systemic corticosteroid effects were not reported with fluticasone nasal spray in controlled trials of up to 6 months' duration, but systemic effects (eg, growth suppression) have been reported with intranasal corticosteroids, including fluticasone propionate, during postmarketing experience.
The most frequent adverse effects of fluticasone propionate nasal spray involve the nasal mucous membranes. Epistaxis or sensations of nasal burning/irritation have been reported in 6-6.9 or 2.4-3.2%, respectively, of patients receiving fluticasone propionate (100-200 ug once daily) in controlled studies. These adverse effects usually are of short duration and rarely require changes in or discontinuance of therapy. Sensations of nasal burning may result from excipients in the commercially available preparation since the frequency and severity of these effects are similar in patients receiving an intranasal placebo vehicle with identical inactive ingredients. In addition, the similar occurrence of adverse nasal effects in fluticasone propionate- or placebo-treated patients with seasonal or perennial rhinitis may result from physical contact and irritation of the characteristically sensitive nasal passages of these patients. Pharyngitis or cough has been reported in 6-7.8 or 3.6-3.8%, respectively, of patients receiving the drug. Symptoms of asthma have occurred in 7.2 or 3.3% of those receiving 100 or 200 ug, respectively, of fluticasone propionate once daily.
Other adverse nasopharyngeal or respiratory effects occurring in 1-3% of patients receiving fluticasone propionate nasal spray include nasal secretions containing blood, nasal discharge, and bronchitis. Sneezing, rhinorrhea, sinusitis, sore throat, throat irritation and dryness, hoarseness, voice changes, alteration or loss of sense of taste and/or smell, nasal congestion or blockage, or nasal dryness has been reported in patients receiving fluticasone propionate nasal spray in controlled studies or during postmarketing surveillance. Nasal septum excoriation, ulceration, or nasal septum crusting also has been reported in patients receiving fluticasone propionate nasal spray. It has been suggested that nasal septum crusting, nasal dryness accompanied by nasal manipulation ("picking"), or nasal bleeding may predispose to the development of nasal perforation, which has been reported rarely with intranasal administration of corticosteroids, including fluticasone propionate. In 2 patients who experienced nasal perforation with fluticasone propionate, both had previous septal surgery that may have increased the risk of nasal perforation.
Localized candidal infections of the nose and/or pharynx have occurred rarely during fluticasone propionate therapy. If a candidal infection is suspected, appropriate local anti-infective therapy and/or discontinuance of intranasal corticosteroid therapy should be considered. Upper respiratory infection also has been reported with intranasal fluticasone propionate therapy, but a causal relationship to the drug has not been established
For more Drug Warnings (Complete) data for Fluticasone (41 total), please visit the HSDB record page.

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Pharmacodynamics
Systemically, in vitro experiments show [DB08906] activates glucocorticoid receptors, inhibits nuclear factor kappa b, and inhibits lung eosinophilia in rats. [DB00588] performs similar activity but is not stated to affect nuclear factor kappa b. [DB00588] as a topical formulation is also associated with vasoconstriction in the skin.

C22H27F3O4S

444.51

500.184

C, 59.45; H, 6.12; F, 12.82; O, 14.40; S, 7.21

90566-53-3

Fluticasone (propionate);80474-14-2

5311101

Typically exists as solid at room temperature

1.3±0.1 g/cm3

568.3±50.0 °C at 760 mmHg

-18.1ºC

297.5±30.1 °C

0.0±3.5 mmHg at 25°C

1.556

3.73

2

8

3

30

861

9

C[C@@]12[C@@](O)(C(=O)SCF)[C@H](C)C[C@H]1[C@@H]1C[C@H](F)C3=CC(C=C[C@]3(C)[C@]1([C@H](C2)O)F)=O

MGNNYOODZCAHBA-GQKYHHCASA-N

InChI=1S/C22H27F3O4S/c1-11-6-13-14-8-16(24)15-7-12(26)4-5-19(15,2)21(14,25)17(27)9-20(13,3)22(11,29)18(28)30-10-23/h4-5,7,11,13-14,16-17,27,29H,6,8-10H2,1-3H3/t11-,13+,14+,16+,17+,19+,20+,21+,22+/m1/s1

S-(fluoromethyl) (6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthrene-17-carbothioate

fluticasone; 90566-53-3; Fluticasona; Fluticasonum; Fluticaps; Fluticaps (TN); Fluticasone (INN); Fluticasone, Inhaled;

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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