Revefenacin   中文名称: 雷芬那辛

M1 ( Ki = 0.42 nM ); M2 ( Ki = 0.32 nM ); M3 ( Ki = 0.18 nM ); M4 ( Ki = 0.56 nM ); M5 ( Ki = 6.7 nM )

Revefenacin 对人 M1、M2、M3、M4 和 M5 受体的 Ki 值分别为 0.42、0.32、0.18、0.56 和 6.7 nM。在功能测定中，revefenacin 被证明是一种功能性拮抗剂，其抑制常数与结合 Kis 相似。 Revefenacin 还可以抑制激动剂诱导的豚鼠离体气管环制剂的收缩，亲和力为 0.1 nM，与测量的 M3 结合 Ki 相似[1]。

在麻醉犬中，瑞芬那新与噻托溴铵和格隆溴铵一起，对乙酰胆碱诱导的支气管收缩产生长达 24 小时的持续抑制。在麻醉大鼠中，吸入瑞芬那新对乙酰甲胆碱诱导的支气管收缩表现出剂量依赖性的 24 小时支气管保护作用。估计的 24 小时效力为 45.0 µg/mL，每日一次给药 7 天后仍能保持支气管保护效力[2]。

Rats: Rats are exposed by inhaling a nebulized solution of either vehicle (sterile water) or revefenacin (3–3000 µg/mL), tiotropium (0.3–300 µg/mL), or glycopyrronium (1–1000 µg/mL) to ascertain the bronchoprotective and antisialagogue potency after a single dose. 24 hours after the dosage, bronchoprotective activity is evaluated. The antisialagogue effect's peak effect time is determined by measuring the inhibition of Pilo 1, 6, or 12 hours after an effective dose of the test compound was inhaled. At this point in time, all subsequent doses are measured[2].

Absorption, Distribution and Excretion
In pharmacokinetic studies, remifenacin was rapidly absorbed with a linear increase in plasma exposure, with Cmax, tmax, and AUC ranging from 0.02–0.15 ng/ml, 0.48–0.51 h, and 0.03–0.36 ng·h/ml, respectively. Remifenacin exhibits very limited bioaccumulation, reaching steady state on day 7. After reaching maximum concentration, remifenacin concentrations show a biphasic decline. This elimination kinetics is characterized by a rapid decrease in plasma concentration followed by a slow, apparent biexponential elimination. Renal elimination of remifenacin is limited, with an average cumulative excretion in the urine of less than 0.2% of the administered dose as unchanged drug. Following intravenous administration, 54% of the dose was excreted in feces and 27% in urine, demonstrating its high hepatobiliary metabolic efficiency.
The reported volume of distribution after intravenous administration of remifenacin is 218 liters, indicating its widespread distribution in tissues.
Renal clearance of remifenacin is negligible; therefore, clearance is not a primary parameter for this drug.
Metabolism/Metabolites

Remifenacin exhibits high metabolic activity and undergoes rapid metabolic turnover after distribution from the lungs. This metabolic process primarily involves enzymatic hydrolysis by CYP2D6, producing its major hydrolytic metabolite THRX-195518.
Biological Half-Life

The apparent terminal half-life of 350 μg of remifenacin is 22.3–70 hours.

Hepatotoxicity
As with other anticholinergic drugs, remifenacin has not been found to be associated with elevated liver enzymes or clinically significant liver injury. Another reason for its high hepatotoxicity may be its low systemic absorption rate when administered via inhalation. Probability Score: E (Unlikely to cause clinically significant liver injury). Drug Category: Anticholinergic Drug

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Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation There is currently no information regarding the use of remifenacin during lactation. Since the oral absorption rate is only 3%, it is unlikely to affect breastfed infants. Prolonged use of remifenacin may reduce milk production or the milk ejection reflex. With prolonged use, signs of reduced milk production (e.g., dissatisfaction, poor weight gain) should be observed. ◉ Effects on Breastfed Infants As of the revision date, no relevant published information was found. ◉ Effects on Lactation and Breast Milk As of the revision date, no relevant published information was found.

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Protein binding
The protein binding rates of remifenac and its active metabolite are 71% and 42%, respectively.

[1]. In vitro characterization of TD-4208, a lung-selective and long-acting muscarinic antagonist bronchodilator (Abstract). Am J Respir Crit Care Med 179:A4553.

[2]. In vivo pharmacological characterization of TD-4208, a novel lung-selective inhaled muscarinic antagonist with sustained bronchoprotective effect in experimental animal models. J Pharmacol Exp Ther. 2013 Aug;346(2):241-50.

Remifenac is a novel tertiary amine biphenyl carbamate drug belonging to the long-acting muscarinic receptor antagonist (LAMA) family. Its unstable primary amide group forms a "soft drug site," allowing for rapid systemic clearance and minimizing systemic adverse reactions. LAMAs belong to the parent class of long-acting inhaled bronchodilators, recommended for maintenance therapy of chronic obstructive pulmonary disease (COPD). Remifenac is the first once-daily nebulized LAMA treatment in the LAMA family. It was developed by Theravance Biopharma and approved by the FDA on November 9, 2018. Remifenac is an anticholinergic drug. Its mechanism of action is as a cholinergic antagonist. Remifenac is a synthetic anticholinergic drug, administered once daily via nebulization for maintenance therapy in patients with chronic obstructive pulmonary disease. Remifenac does not cause elevated liver enzymes or clinically significant acute liver injury.

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Drug Indications
Remifenacin is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD) and is administered as an inhaled solution. COPD is a rapidly developing disease and the third leading cause of death in the United States. The disease is characterized by airflow limitation that is not fully reversible.
FDA Label

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Mechanism of Action
Remifenacin is an inhaled bronchodilator, a muscarinic receptor antagonist, with a long-acting bronchodilatory effect. Studies have shown that remifenacin has a high affinity for all five muscarinic cholinergic receptors and exhibits competitive antagonism. Studies have also shown that remifenacin dissociates significantly more slowly from the M3 muscarinic receptor (hM3) compared to the M2 receptor (hM2), indicating kinetic selectivity for this subtype. This competitive antagonism inhibits acetylcholine-induced airway tissue calcium mobilization and contractile responses.
Furthermore, due to its long-lasting bronchodilatory effect, remifenacin is considered a long-acting muscarinic receptor antagonist and can therefore be administered once daily. This effect is crucial for the treatment of chronic obstructive pulmonary disease (COPD), as the primary goal of treatment is to reduce the frequency and severity of acute exacerbations, which are typically caused by increased cholinergic bronchodilatory tone mediated by muscarinic receptors on the parasympathetic ganglia and airway smooth muscle. Therefore, remifenacin's activity effectively and persistently protects the bronchi from the effects of acetylcholine or methacholine-induced bronchoconstrictive responses.

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Pharmacodynamics
Remifenacin has been reported to produce a sustained, long-lasting bronchodilatory effect with low levels of antimuscarinic side effects. Clinical trials have demonstrated that remifenacin has a long duration of action and low systemic exposure in patients with COPD. Furthermore, reports indicate that a dose of 88 micrograms can produce a clinically effective bronchodilator effect, which can be assessed by forced expiratory volume in one second (FEV1) and continuous pulmonary function testing. In placebo-controlled trials, remifenacin reduced the use of salbutamol emergency inhalers and consistently increased peak expiratory flow, reaching its peak on day 7 and remaining stable. Additionally, remifenacin has been reported to have a superior lung selectivity index and a reduced salivation-promoting effect compared to other long-acting anticholinergic drugs such as glycopyrronium and tiotropium.

C35H43N5O4

597.76

597.331

C, 70.33; H, 7.25; N, 11.72; O, 10.71

864750-70-9

864750-70-9; 864751-51-9 (phosphate); 864751-53-1 (sulfate); 864751-55-3 (oxalate)

11753673

White to off-white solid powder

1.3±0.1 g/cm3

777.5±60.0 °C at 760 mmHg

424.0±32.9 °C

0.0±2.7 mmHg at 25°C

1.645

3.22

108

2

6

11

44

918

0

O=C(NC1C(C2C=CC=CC=2)=CC=CC=1)OC1CCN(CCN(C)C(C2C=CC(CN3CCC(C(N)=O)CC3)=CC=2)=O)CC1

FYDWDCIFZSGNBU-UHFFFAOYSA-N

InChI=1S/C35H43N5O4/c1-38(34(42)29-13-11-26(12-14-29)25-40-19-15-28(16-20-40)33(36)41)23-24-39-21-17-30(18-22-39)44-35(43)37-32-10-6-5-9-31(32)27-7-3-2-4-8-27/h2-14,28,30H,15-25H2,1H3,(H2,36,41)(H,37,43)

[1-[2-[[4-[(4-carbamoylpiperidin-1-yl)methyl]benzoyl]-methylamino]ethyl]piperidin-4-yl] N-(2-phenylphenyl)carbamate

TD-4208; TD4208; GSK-1160724; GSK-1160724; TD 4208; GSK1160724; trade name: Yupelri; TD-4208; GSK 1160724

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (4.18 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。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (4.18 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in 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900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (4.18 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。

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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。