β3-adrenoceptor ( EC50 = 22.4 nM )

体外活性：米拉贝隆浓度依赖性地增加表达人 3-肾上腺素受体 (AR) 的 CHO 细胞中 cAMP 的积累，IA 为 0.8。米拉贝隆对 1- 和 2-AR 几乎没有激动作用。 Mirabegron 浓度依赖性地松弛用 10-6 M 或 10-7 M 卡巴胆碱预收缩的大鼠和人膀胱平滑肌条，EC50 值分别为 5.1 μM 和 0.78 μM。米拉贝隆的最大松弛作用分别是卡巴胆碱的 94.0% 和 89.4%。 Mirabegron 是一种在 NADPH 存在下的 CYP2D6 时间依赖性抑制剂，预孵育 30 分钟后，人肝微粒体中的 IC50 值从 13 μM 降至 4.3 μM。米拉贝隆部分充当 CYP2D6 的不可逆或准不可逆代谢依赖性抑制剂，细胞测定：将 CHO 细胞 (105) 接种到 24 孔培养板的每个孔中并传代培养。三天后，将培养基更换为 250 μL/孔 Hanks 平衡盐溶液，其中含有 0.1 mM 3-异丁基-1-甲基黄嘌呤，pH 7.4。将细胞与每种化合物（终浓度为 10-10 至 10-4 M 的异丙肾上腺素、米拉贝隆、BRL37344 和 CL316,243）在 37°C 下孵育 10 分钟，然后添加 250 μL 停止孵育0.2 M HCl。反应混合物中的cAMP浓度通过使用γ计数器的125I-cAMP测定系统的放射免疫测定来测量。将 50 微升反应混合物与 50 μL 琥珀酰试剂在室温下孵育 10 分钟，然后通过添加 400 μL 缓冲溶液终止反应。将 50 微升琥珀酰化样品与 50 μL 125I-cAMP 和 50 μL 抗 cAMP 抗体在 4°C 下孵育 24 小时。孵育期结束时，添加 250 μL 木炭悬浮液，并在 4°C 下以 2800g 离心 10 分钟。将 250 微升上清液转移至试管中并使用伽玛计数器计数 1 分钟。使用每种化合物的最大反应计算每种 β-肾上腺素受体激动剂相对于异丙肾上腺素的内在活性 (IA)。

米拉贝隆在麻醉大鼠中产生剂量依赖性的节律性膀胱收缩频率降低。 3 mg/kg iv 米拉贝隆可将频率抑制至 2 次/10 分钟。米拉贝隆不会降低膀胱节律收缩的幅度。米拉贝隆降低大鼠初级膀胱传入活动和膀胱微收缩。 Mirabegron（0.3 和 1 mg/kg）抑制 Aδ 纤维响应膀胱充盈的机械敏感单单位传入活动 (SAA)。 C 纤维的 SAA 仅在 1 mg/kg 米拉贝隆治疗时下降。米拉贝隆给药可抑制膀胱等容状态下的平均膀胱压力和微收缩次数。米拉贝隆可有效促进膀胱储存。米拉贝隆剂量依赖性地降低静息膀胱内压。米拉贝隆剂量依赖性地降低非排尿性收缩的频率，被认为是膀胱储存异常反应的指标。米拉贝隆对非排尿收缩幅度、排尿压力、阈压、排尿量、残余量或膀胱容量没有显着影响。

我们评价了（R）-2-（2-氨基噻唑-4-基）-4′-{2-[（2-羟基-2-苯乙基）氨基]-乙基}乙酰苯胺（YM178）的药理特性。YM178增加了表达人β3-肾上腺素受体（AR）的中国仓鼠卵巢（CHO）细胞中环状AMP的积累。半数最大有效浓度（EC50）值为22.4nM。YM178对人β1-和β2-AR的EC50值分别为10000 nM或更高。YM178的内在活性与异丙肾上腺素（非选择性β-AR激动剂）诱导的最大反应之比，对于人β3-AR为0.8，对于人α1-AR为0.1，对于人γ2-AR为0.1。[1]

在 24 孔培养板的每个孔中，放置 10⁵ CHO 细胞并使其生长。三天后，将含有 0.1 mM 3-异丁基-1-甲基黄嘌呤的 pH 7.4 Hanks 平衡盐溶液添加到培养基的每个孔中。在 37°C 下将细胞暴露于每种化合物（异丙肾上腺素、米拉贝隆、BRL37344 和 CL316,243）10 分钟后，添加 250 μL 0.2 M HCl 以结束细胞的孵育。化合物的添加终浓度为 10^-10 至 10^- M。通过使用 ¹²⁵I-cAMP 测定系统和 γ 射线进行放射免疫测定计数器，测定反应混合物中cAMP的浓度。将50微升反应混合物和50μL琥珀酰试剂在室温下孵育10分钟后，加入400μL缓冲溶液终止反应。将 50 微升琥珀酰化样品与 50 μL 125I-cAMP 和 50 μL 抗 cAMP 抗体在 4°C 下孵育 24 小时。孵育期结束后，加入 250 μL 木炭悬浮液，并在 4°C 下以 2800g 离心 10 分钟。将 250 微升上清液转移到试管中后，使用伽马计数器计数一分钟。每种化合物的最大反应用于计算每种 β-肾上腺素受体激动剂相对于异丙肾上腺素的固有活性 (IA)。

Absorption, Distribution and Excretion
The absolute bioavailability of orally administered mirabegron ranges from 29% at a dose of 25 mg to 35% at a dose of 50 mg. The Tmax for the extended-release tablet and suspension formulations are approximately 3.5 hours, while the Tmax for the granule formulation is 4-5 hours. Both Cmax and AUC increase more than dose proportionally - an increase in dose from 50mg to 100mg results in a 2.9- and 2.6-fold increase in Cmax and AUC, respectively, whereas an increase from 50mg to 200mg results in a 8.4- and 6.5-fold increase in Cmax and AUC, respectively. Steady-state concentrations of mirabegron are achieved after approximately 7 days of once-daily administration.
Of a 160mg radiolabeled dose administered to healthy volunteers, approximately 55% of the radioactivity was recovered in the urine and 34% in the feces. Approximately 25% of unchanged mirabegron was recovered in the urine while 0% was recovered in the feces. Renal elimination is achieved primarily via active tubular secretion with some contribution by glomerular filtration.
Following intravenous administration, mirabegron has an apparent steady-state volume of distribution (Vd) of 1670 L indicating extensive distribution.
Total plasma clearance following intravenous administration is approximately 57 L/h, with renal clearance accounting for roughly 25% at approximately 13 L/h.

---

Metabolism / Metabolites
Mirabegron is extensively metabolized via a number of mechanisms, although unchanged parent drug is still the major circulating component following oral administration. Presumed metabolic pathways and their resultant metabolites include amide hydrolysis (M5, M16, M17), glucuronidation (mirabegron O-glucuronide, N-glucuronide, N-carbamoylglucuronide, M12), and secondary amine oxidation or dealkylation (M8, M9, M15), amongst others. The enzymes responsible for the oxidative metabolism of mirabegron are thought to be CYP3A4 and CYP2D6, while the UDP-glucuronosyltransferases responsible for conjugation reactions have been identified as UGT2B7, UGT1A3, and UGT1A8. Other enzymes that may be involved in the metabolism of mirabegron include butylcholinesterase and possibly alcohol dehydrogenase.

---

Biological Half-Life
The mean terminal elimination half-life of mirabegron in adults being treated for overactive bladder is approximately 50 hours. In pediatric patients receiving the granule formulation for the treatment of neurogenic detrusor overactivity, the mean terminal elimination half-life is approximately 26-31 hours.

Hepatotoxicity
In preregistration clinical trials, serum aminotransferase elevations were uncommon and mild in patients treated with mirabegron and rates of serum enzyme elevations were similar to those with placebo treatment. Among several thousands of patients treated, there were no episodes of clinically apparent liver injury. Since its approval and more widescale use, there have not been any published reports of hepatotoxicity attributed to mirabegron. However, the product label for mirabegron mentions occasional elevations in ALT and AST associated with treatment as well as a case of Stevens Johnson syndrome with aminotransferase elevations. Thus, mirabegron may cause hepatic injury as a part of a generalized hypersensitivity reactions.
Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).

---

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of mirabegron during breastfeeding. Because of moderately high protein binding and only relatively low bioavailability, exposure of the breastfed infant is likely to be low. If mirabegron is required by the mother, it is not a reason to discontinue breastfeeding, but until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

---

Protein Binding
Mirabegron is approximately 71% protein-bound in plasma, primarily to albumin and alpha-1-acid glycoprotein.

[1]. Effect of (R)-2-(2-aminothiazol-4-yl)-4'-{2-[(2-hydroxy-2-phenylethyl)amino]ethyl} acetanilide (YM178), a novel selective beta3-adrenoceptor agonist, on bladder function. J Pharmacol Exp Ther. 2007 May;321(2):642-7.

Mirabegron is a monocarboxylic acid amide obtained by formal condensation of the carboxy group of 2-amino-1,3-thiazol-4-ylacetic acid with the anilino group of (1R)-2-{[2-(4-aminophenyl)ethyl]amino}-1-phenylethanol. Used for the treatment of overactive bladder syndrome. It has a role as a beta-adrenergic agonist. It is a member of 1,3-thiazoles, an aromatic amide, a member of ethanolamines and a monocarboxylic acid amide.
Mirabegron is a sympathomimetic beta-3 adrenergic receptor agonist used to relax the smooth muscle of the bladder in the treatment of urinary frequency and incontinence. It is unique amongst overactive bladder treatment options in that, unlike other treatments such as [solifenacin] and [darifenacin], it lacks significant antimuscarinic activity, which is responsible both for the therapeutic effects of these medications and their broad range of adverse effects. Mirabegron has a comparatively favorable adverse effect profile as compared to other available treatment options, and its complementary mechanism to the antimuscarinics that came before it allows for its use alongside solifenacin in refractory cases. Mirabegron first received FDA approval in 2012, under the brand name Myrbetriq, for the treatment of adults with overactive bladder. An extended-release granule formulation was subsequently granted approval in March 2021 for the treatment of pediatric patients with neurogenic detrusor overactivity. Mirabegron is also used in other jurisdictions across the globe, including Canada, the EU, and Japan.
Mirabegron is a beta3-Adrenergic Agonist. The mechanism of action of mirabegron is as an Adrenergic beta3-Agonist, and Cytochrome P450 2D6 Inhibitor, and Cytochrome P450 3A Inhibitor, and P-Glycoprotein Inhibitor.
Mirabegron is a beta-3 adrenergic agonist that is used for treatment of overactive bladder syndrome. Mirabegron has not been implicated in causing liver enzyme elevations or clinically apparent acute liver injury.
Mirabegron is an orally bioavailable agonist of the human beta-3 adrenergic receptor (ADRB3), with muscle relaxing, neuroprotective and potential antineoplastic activities. Upon oral administration, mirabegron binds to and activates ADRB3, which leads to smooth muscle relaxation. Mirabegron also restores sympathetic stimulation in mesenchymal stem cell (MSC) niches, inhibits JAK2-mutated hematopoietic stem cell (HSC) expansion and blocks the progression of myeloproliferative neoplasms (MPNs). Lack of sympathetic stimulation of the MSC and HSC niche is associated with the development of MPNs.

---

Drug Indication
Mirabegron is indicated for the treatment of overactive bladder (OAB) - with symptoms of urge urinary incontinence, urgency, and urinary frequency - either alone or in combination with [solifenacin]. It is also indicated for the treatment of neurogenic detrusor overactivity (NDO) in pediatric patients 3 years of age and older and weighing 35kg or more.
Symptomatic treatment of urgency. Increased micturition frequency and / or urgency incontinence as may occur in adult patients with overactive-bladder syndrome.
Treatment of neurogenic detrusor overactivity
Treatment of idiopathic overactive bladder

---

Mechanism of Action
Mirabegron is a potent and selective agonist of beta-3 adrenergic receptors. The activation of beta-3 receptors relaxes detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle, which increases the bladder's storage capacity thereby alleviating feelings of urgency and frequency.

---

Pharmacodynamics
Mirabegron exerts its pharmacologic effects by forcing bladder smooth muscle to relax, thereby expanding its capacity and relieving urgency. Mirabegron does not appear to adversely affect the mean maximum flow rate or mean detrusor pressure at maximum flow rate in patients with lower urinary tract symptoms and bladder outlet obstruction (BOO), but should be used with in patients with BOO due to reports of significant urinary retention. Furthermore, mirabegron increases both blood pressure and heart rate in a dose-dependent manner and should therefore be used with caution in patients with severely uncontrolled hypertension or others for whom these increases may prove dangerous.

C21H24N4O2S

396.51

396.161

C, 63.61; H, 6.10; N, 14.13; O, 8.07; S, 8.09

223673-61-8

(Rac)-Mirabegron-d5; 1215807-38-7

9865528

White to light yellow solid powder

1.3±0.1 g/cm3

690.0±55.0 °C at 760 mmHg

138-140°C

371.1±31.5 °C

0.0±2.3 mmHg at 25°C

1.681

1.29

128.51

4

6

9

28

467

1

S1C(N([H])[H])=NC(=C1[H])C([H])([H])C(N([H])C1C([H])=C([H])C(=C([H])C=1[H])C([H])([H])C([H])([H])N([H])C([H])([H])[C@@]([H])(C1C([H])=C([H])C([H])=C([H])C=1[H])O[H])=O

PBAPPPCECJKMCM-IBGZPJMESA-N

InChI=1S/C21H24N4O2S/c22-21-25-18(14-28-21)12-20(27)24-17-8-6-15(7-9-17)10-11-23-13-19(26)16-4-2-1-3-5-16/h1-9,14,19,23,26H,10-13H2,(H2,22,25)(H,24,27)/t19-/m0/s1

2-(2-amino-1,3-thiazol-4-yl)-N-[4-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]phenyl]acetamide

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: ≥ 2.08 mg/mL (5.25 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 20.8 mg/mL澄清DMSO储备液加入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: ≥ 2.08 mg/mL (5.25 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 20.8 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。

---

View More

配方 3 中的溶解度: ≥ 2.08 mg/mL (5.25 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 20.8 mg/mL 澄清 DMSO 储备液添加到 900 μL 玉米油中并混合均匀。

---

配方 4 中的溶解度:

Mirabegron (10 mg/ml) dissolved in DMSO (50%, vol%) and polyethylene glycol (50%, vol%)

---

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。