Corticosteroid (Kd = 0.3 nM)

通过计量雾化喷雾泵，将糠酸氟替卡松作为微粉化糠酸氟替卡松水悬浮液以鼻喷雾剂的形式局部施用于鼻粘膜[1]。糠酸氟替卡松可以有效防止对培养的人肺上皮细胞的不当刺激[1]。

在体外，糠酸氟替卡松 99.4% 与氧化剂结合，另外的研究表明，该药物在被吸收后会发挥广泛的作用。由于只有未结合的氧化剂药物才能作用于受体位点，因此蛋白质极其重要。糠酸氟替卡松主要通过细胞色素 P450 同工酶 (CYP) 3A4 从体内清除，细胞色素 P450 同工酶 (CYP) 3A4 会处理药物并将其转化为 17β-氨基磺酸盐 (M10)，这是一种有效结合降血糖激素受体的药物。 ..只有少量糠酸氟替卡松通过粪便排出，这是其大部分排泄的地方[1]。

糠酸氟替卡松具有高受体亲和力，平衡解离常数低（kd=0.3 nmol/L），相对受体亲和力（2989）大于糠酸莫米松（2244）、丙酸氟替卡森（1775）、倍氯米松17-单丙酸酯（1345）、环索奈德有效成分（1212）和布地奈德（855）[1]
一些体外研究表明，FF在抑制肿瘤坏死因子合成和作用方面比其他皮质类固醇表现出更大的效力。它在防止不同刺激对培养的人肺上皮细胞的损伤方面也更有效。实验研究表明，FF的抗炎活性比丙酸氟替卡松更强、更快[1]。

哮喘是一种复杂的疾病，临床表现从轻到重不等。尽管已有哮喘识别和治疗指南，但仍有一部分患者未得到控制。包括吸入皮质类固醇（ICS）和长效B2肾上腺素受体激动剂（LABA）的联合治疗已被建议用于控制哮喘。在这项研究中，使用免疫细胞化学（ICC），与中度哮喘患者和健康对照组相比，用糠酸氟替卡松（FF）、维拉托醇（V）和FF/V联合治疗的重度哮喘患者的CD4 T细胞中证实了T-bet的表达。首先，使用CD4 T细胞分离试剂盒从12名患者和对照的PBMC中分离CD4 T淋巴细胞。随后，将分离的CD4 T细胞与FF、V和FF/V一起培养1小时。为了完成ICC，将细胞与抗T-bet抗体一起孵育，然后用HRP结合的第二抗体染色。使用光学显微镜评估T-bet的表达。使用R 3.5.2软件进行统计分析，并通过ggplot2 3.1.0软件包进行可视化。在接受FF和FF/V治疗的中度哮喘患者的CD4 T细胞中观察到T-bet表达显著增加。这一结论将是导致患者严重哮喘和中度哮喘的不同机制，以及对新疗法的需求。对不同哮喘表型进行进一步的分子研究将对哮喘治疗具有指导意义[2]。

Allergic rhinitis (AR) is a prevalent disease with great morbidity and significant societal and economic burden. Intranasal corticosteroids are recommended as first-line therapy for patients with moderate-to-severe disease, especially when nasal congestion is a major component of symptoms. To compare the efficacy and safety profile of different available intranasal corticosteroids for the treatment of AR, it is important to understand their different structures and pharmacokinetic and pharmacodynamic properties. Knowledge of these drugs has increased tremendously over the last decade. Studies have elucidated mechanisms of action, pharmacologic properties, and the clinical impact of these drugs in allergic respiratory diseases. Although the existing intranasal corticosteroids are already highly efficient, the introduction of further improved formulations with a better efficacy/safety profile is always desired. Fluticasone furoate nasal spray is a new topical corticosteroid, with enhanced-affinity and a unique side-actuated delivery device. As it has high topical potency and low potential for systemic effects, it is a good candidate for rhinitis treatment [1].

---

After single- and multiple-dose intranasal administration, plasma fluticasone furoate concentrations are below the lower limit of quantification in most patients (Allen et al 2007; Hughes et al 2007; Martin 2007). One study showed that only 2% of samples from patients receiving 110 μg of FF had quantifiable plasma drug concentrations (Martin 2007). Systemic bioavailability is determined by the sum of 2 components, including the portion of the drug that is absorbed via the nasal mucosa plus the portion that is swallowed. The last one is the major route for circulation, what makes the first-pass hepatic metabolism after drug absorption in the gastrointestinal tract very important[1].

Absorption, Distribution and Excretion
Fluticasone furoate plasma levels may not predict therapeutic effect. Peak plasma concentrations are reached within 0.5 to 1 hour. Absolute bioavailability of fluticasone furoate when administrated by inhalation was 13.9%, primarily due to absorption of the inhaled portion of the dose delivered to the lung. Oral bioavailability from the swallowed portion of the dose is low (approximately 1.3%) due to extensive first-pass metabolism. Systemic exposure (AUC) in subjects with asthma was 26% lower than observed in healthy subjects. Following repeat dosing of inhaled fluticasone furoate, steady state was achieved within 6 days with up to 2.6-fold accumulation. Intranasal exposure of fluticasone furoate also results in patients swallowing a larger portion of the dose.
Following intravenous dosing with radiolabeled fluticasone furoate, mass balance showed 90% of radiolabel in the feces and 2% in the urine. Following oral dosing, radiolabel recovered in feces was 101% of the total dose, and that in urine was approximately 1% of the total dose.
Following intravenous administration to healthy subjects, the mean volume of distribution at steady state was 661 L. A study of 24 healthy Caucasian males showed a volume of distribution at steady state of 704L following intravenous administration.
Following intravenous administration to healthy subjects, fluticasone furoate was cleared from systemic circulation principally by hepatic metabolism via CYP3A4 with a total plasma clearance of 65.4 L/hr. A study of 24 healthy Caucasian males also showed a clearance of 71.8L/h following intravenous administration.

---

Metabolism / Metabolites
Fluticasone furoate is cleared from systemic circulation principally by hepatic metabolism via CYP3A4 to metabolites with significantly reduced corticosteroid activity. There was no in vivo evidence for cleavage of the furoate moiety resulting in the formation of fluticasone. Fluticasone furoate is also hydrolyzed at the FIVE-S-fluoromethyl carbothioate group, forming an inactive metabolite.

---

Biological Half-Life
Following repeat-dose inhaled administration, the plasma elimination phase half-life averaged 24 hours. A study of 24 healthy Caucasian males showed a half-life of 13.6 hours following intravenous administration and 17.3-23.9 hours following inhalation.

Protein Binding
Fluticasone furoate is >99% protein bound in serum and may be as high as 99.6%, predominantly to albumin (96%) and α1-acid glycoprotein (90%).

[1]. Fluticasone furoate nasal spray in the treatment of allergic rhinitis. Ther Clin Risk Manag. 2008 Apr;4(2):465-72.

[2]. Asthma phenotypes and T-bet protein expression in cells treated with Fluticasone Furoate/Vilanterol. Pulm Pharmacol Ther. 2020 Feb;60:101886.

Fluticasone furoate 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 2-furoyl substituent at position 17. Used in combination with vilanterol trifenate for treatment of bronchospasm associated with chronic obstructive pulmonary disease. It has a role as an anti-allergic agent, a prodrug and an anti-asthmatic drug. It is an 11beta-hydroxy steroid, a corticosteroid, a fluorinated steroid, a steroid ester, a 2-furoate ester, 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 furoate is a synthetic glucocorticoid available as an inhaler and nasal spray for various inflammatory indications. Fluticasone furoate was first approved in 2007.
Fluticasone Furoate is the furoate salt form of fluticasone, a synthetic trifluorinated glucocorticoid receptor agonist with anti-allergic, anti-inflammatory and anti-pruritic effects. Upon administration, fluticasone binds to and activates glucocorticoid receptor, resulting in the activation of lipocortin. Lipocortin, in turn, inhibits cytosolic phospholipase A2 and the cascade of reactions involved in the synthesis of inflammatory mediators, such as prostaglandins and leukotrienes. Secondly, mitogen-activated protein kinase (MAPK) phosphatase 1 is induced, which leads to dephosphorylation and inactivation of Jun N-terminal kinase and directly inhibits c-Jun mediated transcription. Finally, transcriptional activity of nuclear factor (NF)-kappa-B is blocked, thereby inhibiting the transcription of cyclooxygenase 2 (COX-2), which is essential for prostaglandin production.
See also: Fluticasone (has active moiety); Fluticasone furoate; vilanterol trifenatate (component of) ... View More ...

---

Drug Indication
Fluticasone furoate is indicated for once-daily maintenance (i.e. prophylactic) treatment of asthma in patients ≥5 years old. Fluticasone furoate is available in two combination medications - one in combination with [vilanterol] and one in combination with both vilanterol and [umeclidinium]- which are both indicated for the management of chronic obstructive pulmonary disease (COPD) and for the treatment of asthma in patients ≥18 years old for the vilanterol-umeclidinium-fluticasone product and ≥5 years old for the vilanterol-fluticasone product. Fluticasone furoate is available over the counter as a nasal spray for the symptomatic treatment of hay fever and other upper respiratory allergies in patients ≥2 years old.
FDA Label
Adults, adolescents (12 years and over) and children (6-11 years). Avamys is indicated for the treatment of the symptoms of allergic rhinitis.
Adults, adolescents (12 years and over) and children (6 - 11 years). Alisade is indicated for the treatment of the symptoms of allergic rhinitis.

---

Mechanism of Action
Fluticasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. The clinical relevance of these findings is unknown. The precise mechanism through which fluticasone furoate affects asthma symptoms is not known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. Specific effects of fluticasone furoate demonstrated in in vitro and in vivo models included activation of the glucocorticoid response element, inhibition of pro-inflammatory transcription factors such as NFkB, and inhibition of antigen-induced lung eosinophilia in sensitized rats. These anti-inflammatory actions of corticosteroids may contribute to their efficacy.

C27H29O6F3S

538.57576

538.163

C, 60.21; H, 5.43; F, 10.58; O, 17.82; S, 5.95

397864-44-7

Fluticasone (propionate);80474-14-2;Fluticasone furoate-d3

9854489

White to off-white solid powder

1.4±0.1 g/cm3

625.2±55.0 °C at 760 mmHg

250-252

331.9±31.5 °C

0.0±1.9 mmHg at 25°C

1.584

4.01

119.11

1

10

6

37

1080

9

C[C@@H]1C[C@H]2[C@@H]3C[C@@H](C4=CC(=O)C=C[C@]4(C)[C@]3([C@H](C[C@]2(C)[C@]1(C(=O)SCF)OC(=O)C5=CC=CO5)O)F)F

XTULMSXFIHGYFS-VLSRWLAYSA-N

InChI=1S/C27H29F3O6S/c1-14-9-16-17-11-19(29)18-10-15(31)6-7-24(18,2)26(17,30)21(32)12-25(16,3)27(14,23(34)37-13-28)36-22(33)20-5-4-8-35-20/h4-8,10,14,16-17,19,21,32H,9,11-13H2,1-3H3/t14-,16+,17+,19+,21+,24+,25+,26+,27+/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 furan-2-carboxylate

Avamys; Veramyst; Fluticasone furoate; 397864-44-7; Veramyst; Avamys; Allermist; Furamist; Arnuity Ellipta; Alisade; Allermist

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 : ~100 mg/mL (~185.67 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (4.64 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

---

配方 2 中的溶解度: ≥ 2.5 mg/mL (4.64 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

---

请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。