体外活性：奈比洛尔对兔肺膜制剂中的 β1-肾上腺素能受体位点表现出高亲和力和选择性（Ki 值 = 0.9 nM，β2/β1 比率 = 50）。在存在 CGP 207.12 A（300 nM，Kiβ2）或 ICI 118.551（50 nM，Kiβ1）的情况下，奈必洛尔表现出 β1-肾上腺素受体选择性，通过与 3H-CGP 12.1777 的竞争实验判断，Ki(β2)/Ki(β1) 值为 40.7 ）。奈必洛尔以浓度和时间依赖性方式减少人冠状动脉平滑肌细胞 (haCSMC) 和内皮细胞 (haEC) 的细胞增殖。奈比洛尔治疗 7 天导致 haCSMC 细胞生长显着减少，IC50 为 6.1 μM，并抑制生长因子 PDGF-BB、bFGF 和 TGFβ 刺激的加速 haCSMC 增殖，IC50 值分别为 6.8 μM、6.4 μM 和 7.7 μM 。奈必洛尔 (10-5 M) 对 haCSMC 处理 48 小时，诱导 23% 的中度细胞凋亡，S 期细胞数量从 16% 减少至 5%。奈必洛尔孵育期间，HaCEs 的 NO 形成增加，而内皮素-1 转录和分泌受到抑制。细胞测定：将细胞[人冠状平滑肌细胞（haCSMC）和内皮细胞（haEC）]暴露于不同浓度的奈必洛尔（10-7~10-5 M）中1、2、4、7和14天。通过溴脱氧尿苷 (BrdU) 掺入分析细胞增殖，并通过 PI 或膜联蛋白 V 染色检测细胞凋亡。

对心肌梗塞 (MI) 大鼠给予奈必洛尔（首先在再灌注 10 分钟内静脉注射，然后口服）可减少心肌细胞凋亡，这是由 NO 调节介导的。奈必洛尔可显着防止左心室 (LV) 压力变化，减少心肌细胞总数和局部凋亡。奈必洛尔治疗可轻微降低心肌梗死大鼠的平均血压（MBP），但不显着。

将奈比洛尔 (10-7~10-5 M) 以不同浓度添加到人冠状平滑肌细胞 (haCSMC) 和内皮细胞 (haEC) 中，持续 1、2、4、7 和 14 天。溴脱氧尿苷 (BrdU) 掺入用于分析细胞增殖，而 PI 或膜联蛋白 V 染色用于识别细胞凋亡。

Absorption, Distribution and Excretion
The absorption of nebivolol is not affected by food. Nebivolol has a Tmax of 1.5-4 hours. Bioavailability can range from 12-96% for extensive to poor CYP2D6 metabolizers. For a 20mg dose, d-nebivolol has a Cmax of 2.75±1.55ng/mL, l-nebivolol has a Cmax of 5.29±2.06ng/mL, both enantiomers have a Cmax of 8.02±3.47ng/mL, and nebivolol glucuronides have a Cmax of 68.34±44.68ng/mL. For a 20mg dose, d-nebivolol has an AUC of 13.78±15.27ng\*h/mL, l-nebivolol has an AUC of 27.72±15.32ng\*h/mL, both enantiomers have an AUC of 41.50±29.76ng\*h/mL, and nebivolol glucuronides have an AUC of 396.78±297.94ng\*h/mL.
In extensive CYP2D6 metabolizers, 38% is eliminated in the urine and 44% in the feces. In poor CYP2D6 metabolizers, 67% is eliminated in the urine and 13% in the feces. <1% of a dose is excreted as the unmetabolized drug.
For a 20mg dose, d-nebivolol has an apparent volume of distribution of 10,290.81±3911.72L, l-nebivolol has an apparent volume of distribution of 8,066.66±4,055.50L, and both enantiomers together have a volume of distribution of 10,423.42±6796.50L.
For a 20mg dose, the clearance of d-nebivolol is 1241.63±749.77L/h, l-nebivolol is 435.53±180.93L/h, and both enantiomers is 635.31±300.25L/h.

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Metabolism / Metabolites
Nebivolol is metabolized mainly by glucuronidation and CYP2D6 mediated hydroxylation. Metabolism involves n-dealkylation, hydroxylation, oxidation, and glucuronidation. Aromatic hydroxyl and acyclic oxide metabolites are active, while n-dealkylated and glucuronides are inactive.

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Biological Half-Life
d-nebivolol has a half life of 12 hours in CYP2D6 extensive metabolizers and 19 hours in poor metabolizers.

Hepatotoxicity
Mild-to-moderate elevations in serum aminotransferase levels occur in less than 2% of patients on beta-blockers and are usually transient and asymptomatic, resolving even with continuation of therapy. There is no information on the rates of ALT elevations during nebivolol therapy. Despite its use in several large clinical trials, nebivolol has not been linked to cases of clinically apparent liver injury.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because no information is available on the use of nebivolol during breastfeeding, 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.

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Protein Binding
Nebivolol is 98% bound to plasma proteins, mostly to serum albumin.

[1]. Nebivolol: the somewhat-different beta-adrenergic receptor blocker. J Am Coll Cardiol. 2009 Oct 13;54(16):1491-9.

[2]. Effects of nebivolol on proliferation and apoptosis of human coronary artery smooth muscle and endothelial cells. Cardiovasc Res. 2001 Feb 1;49(2):430-9.

2,2'-iminobis[1-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethanol] is a member of the class of chromanes that is 2,2'-iminodiethanol in which one hydrogen attached to each hydroxy-bearing carbon is replaced by a 6-fluorochroman-2-yl group. It is an organofluorine compound, a secondary amino compound, a secondary alcohol, a diol and a member of chromanes.
Nebivolol is a racemic mixture of 2 enantiomers where one is a beta adrenergic antagonist and the other acts as a cardiac stimulant without beta adrenergic activity. Treatment with nebivolol leads to a greater decrease in systolic and diastolic blood pressure than [atenolol], [propranolol], or [pindolol]. Nebivolol and other beta blockers are generally not first line therapies as many patients are first treated with thiazide diuretics. Nebivolol was granted FDA approval on 17 December 2007.
Nebivolol is a beta-blocker and antihypertensive medication that has additional vasodilatory activity mediated by nitric oxide release. Nebivolol has yet to be linked to instances of clinically apparent liver injury.
Nebivolol is a beta-1 adrenergic receptor antagonist with antihypertensive and vasodilatory activity. Nebivolol binds to and blocks the beta-1 adrenergic receptors in the heart, thereby decreasing cardiac contractility and rate. This leads to a reduction in cardiac output and lowers blood pressure. In addition, nebivolol potentiates nitric oxide (NO), thereby relaxing vascular smooth muscle and exerting a vasodilatory effect.
A cardioselective ADRENERGIC BETA-1 RECEPTOR ANTAGONIST (beta-blocker) that functions as a VASODILATOR through the endothelial L-arginine/ NITRIC OXIDE system. It is used to manage HYPERTENSION and chronic HEART FAILURE in elderly patients.
See also: Nebivolol Hydrochloride (has salt form).

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Drug Indication
Nebivolol is indicated to treat hypertension.

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Mechanism of Action
Nebivolol is a highly selective beta-1 adrenergic receptor antagonist with weak beta-2 adrenergic receptor antagonist activity. Blocking beta-1 adrenergic receptors by d-nebivolol leads to decreased resting heart rate, exercise heart rate, myocardial contracility, systolic blood pressure, and diastolic blood pressure. The selectivity of d-nebivolol limits the magnitude of beta blocker adverse effects in the airways or relating to insulin sensitivity. Nebivolol also inhibits aldosterone, and beta-1 antagonism in the juxtaglomerular apparatus also inhibits the release of renin. Decreased aldosterone leads to decreased blood volume, and decreased renin leads to reduced vasoconstriction. l-nebivolol is responsible for beta-3 adrenergic receptor agonist activity that stimulates endothelial nitric oxide synthase, increasing nitric oxide levels; leading to vasodilation, decreased peripheral vascular resistance, increased stroke volume, ejection fraction, and cardiac output. The vasodilation, reduced oxidative stress, and reduced platelet volume and aggregation of nebivolol may lead to benefits in heart failure patients.

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Pharmacodynamics
Nebivolol is a selective beta-1 adrenergic receptor antagonist that decreases vascular resistance, increases stroke volume and cardiac output, and does not negatively affect left ventricular function. It has a long duration of action as effects can be seen 48 hours after stopping the medication and a wide therapeutic window as patients generally take 5-40mg daily. Patients should not abruptly stop taking this medication as this may lead to exacerbation of coronary artery disease. Diabetic patients should monitor their blood glucose levels as beta blockers may mask signs of hypoglycemia.

C22H26CLF2NO4

441.9

405.175

C, 65.17; H, 6.22; F, 9.37; N, 3.45; O, 15.78

118457-14-0

Nebivolol hydrochloride; 152520-56-4; (Rac)-Nebivolol; 99200-09-6; (rac)-Nebivolol-d4; 1219407-55-2

71301

Solid powder

1.3±0.1 g/cm3

600.5±55.0 °C at 760 mmHg

223.0-228.0

316.9±31.5 °C

0.0±1.8 mmHg at 25°C

1.581

3.67

100.62

3

7

6

29

483

0

FC1=CC=C2C(CC[C@]([C@@H](O)CNC[C@H](O)[C@@]3([H])CCC(C=C(F)C=C4)=C4O3)([H])O2)=C1

KOHIRBRYDXPAMZ-YHDSQAASSA-N

InChI=1S/C22H25F2NO4/c23-15-3-7-19-13(9-15)1-5-21(28-19)17(26)11-25-12-18(27)22-6-2-14-10-16(24)4-8-20(14)29-22/h3-4,7-10,17-18,21-22,25-27H,1-2,5-6,11-12H2/t17-,18-,21-,22+/m0/s1

(1S)-1-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-[[(2S)-2-[(2R)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-hydroxyethyl]amino]ethanol

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)

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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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。