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 administration of [DB08906] results in the patient swallowing the majority of the dose. However, its absorption rate is low and its metabolic rate is high, therefore systemic exposure is negligible. Intranasal bioavailability is 0.50%, and oral bioavailability is 1.26%. Inhalation bioavailability is 13.9%. A study of 24 healthy Caucasian men showed inhalation bioavailability ranging from 6.3% to 18.4%. [DB00588] has intranasal bioavailability <2% and oral bioavailability <1%. Intranasal administration results in the majority of the dose being swallowed. Local absorption of [DB00588] is extremely 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 inhalation bioavailability of 9.0%. [DB08906] ≥90% is excreted in feces, and 1-2% in urine. [DB00588] Primarily excreted in feces, <5% in urine. [DB08906] Steady-state volume of distribution after intravenous administration is 608 L. Other reports indicate a mean steady-state volume of distribution of 661 L. A study of 24 healthy Caucasian men showed a steady-state volume of distribution of 704 L after intravenous administration. The volume of distribution of [DB00588] via intravenous injection 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 [DB08906] is 57.8 L/h. A study of 24 healthy Caucasian men showed a clearance of 71.8 L/h after intravenous administration. The clearance of [DB00588] is 1093 mL/min. Another study of 24 healthy Caucasian men showed a clearance of 63.9 L/h after intravenous administration.
Absorption of fluticasone propionate aqueous nasal spray into the respiratory and gastrointestinal tracts is very low. Indirect calculations indicate that the absolute systemic bioavailability of intranasal fluticasone propionate is less than 2%. Most intranasally administered corticosteroids are swallowed and undergo extensive first-pass metabolism in the liver. In patients with allergic rhinitis treated with intranasal fluticasone propionate for 2–3 weeks, plasma concentrations exceeding the detection limit (50 pg/mL) are only observed at doses exceeding the recommended dose, and even in these cases, only in a few low-concentration samples.
Limited data from oral administration studies of radiolabeled fluticasone propionate indicate poor gastrointestinal absorption and rapid first-pass metabolism in the liver. Preliminary data from a dose-range study showed that plasma levels of unmetabolized fluticasone propionate increase with dose after oral administration, but the average bioavailability after oral administration of 1–40 mg of radiolabeled drug is approximately 1% or less. In several healthy subjects, after oral administration of 1 mg or 16 mg of radiolabeled fluticasone propionate, peak plasma radioactivity (expressed as fluticasone propionate equivalents) was reached within 0.5–6 hours, with average values of approximately 1.3 ng/mL and 9.1 ng/mL, respectively. Since unmetabolized fluticasone propionate was not detected in plasma for up to 6 hours after another oral administration of unlabeled fluticasone propionate, it is presumed that the plasma radioactivity observed after administration of the radiolabeled drug is a metabolite of fluticasone propionate. Studies have shown that small amounts (50–170 pg/mL) of fluticasone propionate are present in plasma within 6–24 hours after administration in these patients, which may represent rectal reabsorption of unmetabolized drug. The extent of percutaneous absorption of topical corticosteroids depends on a variety of factors, including the excipients and the integrity of the epidermal barrier. Occlusive dressings can enhance drug penetration. Topical corticosteroids can be absorbed from normal, intact skin. Skin inflammation and/or other disease processes can increase percutaneous absorption. For more complete data on the absorption, distribution, and excretion of fluticasone (14 in total), please visit the HSDB record page. Metabolites/Metabolites [DB08906] and [DB00588] are eliminated from the liver via cytochrome P450 3A4. Both are hydrolyzed at the pentafluoromethyl thiocarbamate group to produce inactive metabolites. Fluticasone propionate is rapidly metabolized in the liver by the cytochrome P-450 isoenzyme CYP3A4; the major metabolite is an inactive 17β-carboxylic acid derivative. ...Of the total radioactivity recovered in urine, 18% is the inactive 17β-carboxylic acid derivative of fluticasone propionate, 12% is a less polar metabolite, and the remainder is a more polar metabolite. The 17β-carboxylic acid metabolite of fluticasone propionate accounts for 3-40% of fecal excretion.
This inactive 17β-carboxylic acid derivative has a lower affinity for human lung cell glucocorticoid receptors (approximately 1/2000th that of the parent drug) than the parent drug in in vitro studies, and its pharmacological activity in animal studies is negligible. Other metabolites detected in cultured human hepatocellular carcinoma cells have not been detected in humans.
In in vitro studies, no metabolites of fluticasone propionate were detected when radiolabeled fluticasone propionate was incubated with human skin homogenate.
Biological half-life
Intranasal administration [DB08906] is 15.1 hours, and the inhaled formulation is 24 hours. A study of 24 healthy Caucasian men showed a half-life of 13.6 hours after intravenous injection and 17.3–23.9 hours after inhalation. The half-life after intravenous injection is 7.8 hours [DB00588]. Another study involving 24 healthy Caucasian men showed a half-life of 14.0 hours after intravenous injection and 10.8 hours after inhalation. Following intravenous injection of 1 mg fluticasone propionate in healthy volunteers, the pharmacokinetics exhibited a multi-exponential decay, with a mean terminal half-life of 7.2 hours (range: 3.2 to 11.2 hours). The apparent elimination half-life after intravenous injection of fluticasone propionate was approximately 3 hours.

Effects During Pregnancy and Lactation
◉ Overview of Medication Use During Lactation
The safety of topical fluticasone during lactation has not been studied. Since only large-area application of potent corticosteroids is likely to have systemic effects on the mother, short-term topical application of corticosteroids is unlikely to pose a risk to the nursing infant through breast milk. However, it is advisable to use the least potent medication on the smallest possible area of skin. It is especially important to ensure that the infant's skin does not come into direct contact with the treated area. Current guidelines allow for the application of topical corticosteroids to the nipples immediately after breastfeeding to treat eczema, with the nipples gently cleaned before breastfeeding. Only water-soluble creams or gels should be applied to the breasts, as ointments may expose the infant to high concentrations of mineral oil through licking.
◉ Effects on Breastfed Infants
A mother applied a topical corticosteroid (isofluprednisolone acetate) with high mineralocorticoid activity to her nipples, resulting in QT interval prolongation, Cushing's syndrome-like symptoms, severe hypertension, growth retardation, and electrolyte imbalance in her 2-month-old breastfed infant. The mother had been using the cream due to nipple pain since the infant's birth.
◉ Effects on Lactation and Breast Milk
No published information found as of the revision date.
◉ Summary of Medication Use During Lactation
Although measurements were not performed, the amount of inhaled corticosteroids absorbed into the mother's bloodstream and excreted into breast milk is likely too small to affect breastfed infants. Expert opinion is that inhaled, nasal, and oral corticosteroids are acceptable during lactation. See also topical fluticasone.
◉ Effects on Breastfed Infants
Currently, there are no reports on the use of corticosteroids.
◉ Effects on Lactation and Breast Milk
As of the revision date, no relevant published information was found.

---

Protein Binding
[DB08906] has a protein binding rate in serum >99%, up to 99.6%. [DB00588] has a protein binding rate in serum of 99%. Topical application of [DB00588] has a protein binding rate in serum of only 91%.

---

Drug Interactions
A drug interaction study in healthy subjects showed that ritonavir (a potent cytochrome P450 3A4 inhibitor) significantly increased plasma exposure to fluticasone propionate, thereby significantly reducing serum cortisol concentrations.
In a placebo-controlled crossover study of 8 healthy volunteers, a single inhaled dose of fluticasone propionate combined with multiple doses of ketoconazole to steady state resulted in increased plasma exposure to fluticasone propionate and a decreased plasma cortisol AUC, but had no effect on urinary cortisol excretion. Caution should be exercised when fluticasone propionate is used in combination 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
Androsadiene
Fluticasone propionate nasal spray is indicated for the treatment of nasal symptoms of seasonal and perennial allergic and non-allergic rhinitis in adults and children 4 years of age and older. /US product label includes/
Fluticasone propionate cream is a moderately potent corticosteroid indicated for the relief of inflammatory and itchy symptoms of corticosteroid-responsive dermatitis. Fluticasone propionate cream may be used with caution in children 3 months of age and older. The safety and efficacy of this drug with continuous use for more than 4 weeks in this population have not been established. /US product label includes/
Fluticasone propionate ointment is a moderately potent corticosteroid indicated for the relief of inflammatory and itchy symptoms of corticosteroid-sensitive dermatitis in adult patients. /US product label includes/
For more complete data on the therapeutic uses of fluticasone (6 types), please visit the HSDB record page.

---

Drug Warnings
Intranasal fluticasone propionate is generally well tolerated. Adverse reactions to intranasal fluticasone propionate are usually mild and localized, resolving without specific treatment. The manufacturer states that no systemic corticosteroid side effects were reported with fluticasone nasal spray in controlled trials lasting up to 6 months; however, post-marketing experience suggests that systemic side effects (such as growth inhibition) have been reported with intranasal corticosteroids, including fluticasone propionate. The most common adverse reaction to fluticasone propionate nasal spray involves the nasal mucosa. In controlled studies, 6-6.9% and 2.4-3.2% of patients treated with fluticasone propionate (100-200 mcg once daily) reported nasal bleeding or nasal burning/irritation, respectively. These adverse reactions are usually short-lived and rarely require modification or discontinuation of treatment. Since patients using intranasal placebos containing the same inactive ingredient experienced similar frequency and severity of these adverse reactions, nasal burning may be due to excipients in commercially available formulations. Furthermore, similar nasal adverse reactions in patients with seasonal or perennial rhinitis receiving fluticasone propionate or placebo may be due to direct contact and irritation of the drug with the sensitive nasal passages characteristic of these patients. Pharyngitis or cough has been reported in 6-7.8% and 3.6-3.8% of patients receiving this drug, respectively. Asthma symptoms were reported in 7.2% and 3.3% of patients receiving once-daily fluticasone propionate at 100 mcg and 200 mcg, respectively. Other nasopharyngeal or respiratory adverse reactions, occurring in 1-3% of fluticasone propionate nasal spray users, include bloody nasal discharge, runny nose, and bronchitis. In controlled studies or post-marketing surveillance, patients treated with fluticasone propionate nasal spray have reported adverse reactions including sneezing, runny nose, sinusitis, sore throat, throat irritation and dryness, hoarseness, voice changes, altered or lost sense of taste and/or smell, nasal congestion or obstruction, and nasal dryness. Nasal septal abrasion, ulceration, or crusting have also been reported in patients treated with fluticasone propionate nasal spray. Studies have shown that nasal septal crusting, nasal dryness with nasal manipulation ("nose picking"), or epistaxis may induce nasal perforation, while the incidence of nasal perforation is lower with intranasal use of corticosteroids, including fluticasone propionate. Two patients who developed nasal perforation after using fluticasone propionate had previously undergone nasal septum surgery, which may have increased the risk of nasal perforation. Localized nasal and/or pharyngeal candidiasis is rare during fluticasone propionate treatment. If Candida infection is suspected, appropriate topical anti-infective therapy and/or discontinuation of intranasal corticosteroid therapy should be considered. There are also reports of upper respiratory tract infections caused by intranasal fluticasone propionate treatment, but a causal relationship with the drug has not been established. For more complete data on drug warnings (of 41) for fluticasone, please visit the HSDB record page.

---

Pharmacodynamics
In vitro studies have shown that [DB08906] activates glucocorticoid receptors, inhibits nuclear factor kappa B, and suppresses eosinophilia in rat lungs. [DB00588] has similar activity, but its effect on nuclear factor kappa B is not described. [DB00588] As a topical preparation, it is also associated with vasoconstriction of 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.

---

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).

View More

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)

---

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).

View More

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

---

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.

---

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