β1 adrenoceptor

美托洛尔（0-1000 μg/mL；24-72 小时）对 MOLT-4 和 U937 细胞的细胞毒性作用具有剂量和时间依赖性 [3]。

在 ApoE−/− 小鼠中，美托洛尔（2.5 mg/kg/h；输注；11 周）可减少动脉粥样硬化和促炎细胞因子 [1]。美托洛尔（15 mg/kg/q12h；ig；5 天）在由柯萨奇病毒 B3 引起的病毒性心肌炎小鼠模型中显示出抗病毒和抗炎特性 [2]。在患有冠状动脉微栓塞（CME）的大鼠中，美托洛尔（2.5 mg/kg；静脉注射；3次推注）有效防止心肌细胞死亡并减少活化的caspase-9蛋白表达[4]。

细胞毒性测定 [3]
细胞类型： U937 和 MOLT-4 细胞
测试浓度： 1、10、50、100、500 和 1000 μg/ mL
孵育持续时间：24、48 和 72 小时
实验结果：孵育的 U937 和 MOLT -4 细胞的活力显着降低在 1000 μg/mL (3740.14μM) 浓度下孵育 48 小时 (hrs (hours)) 在 ≥500 μg/ml (≥1870.07μM) 浓度下孵育 72 小时 (hrs (hrs) 后，U937 细胞的活力显着降低小时）），并且在孵育 72 小时后，U937 细胞的活力显着降低。 hrs（小时）后，MOLT4细胞浓度≥100 μg/ml（≥374.01μM）。

Animal/Disease Models: Male ApoE−/− mice [1]
Doses: 2.5 mg/kg/h
Route of Administration: via mini-osmotic pump, 11 weeks
Experimental Results: Thoracic aorta atherosclerotic plaque area Dramatically diminished, serum TNFα and chemokine CXCL1, and diminished macrophage content in plaques.

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Animal/Disease Models: Balb/c mouse, coxsackie virus B3 (CVB3)-induced viral myocarditis (VMC) model [2]
Doses: 15 mg/kg/q12h
Route of Administration: po (oral gavage), for 5 days
Experimental Results: CVB3 infection-induced reduction in VMC pathology score protects myocardium from viral damage by reducing serum cTn-I levels. Reduce myocardial pro-inflammatory cytokine levels and increase anti-inflammatory cytokine expression. Myocardial virus titers were Dramatically diminished.

Absorption, Distribution and Excretion
When metoprolol is administered orally, it is almost completely absorbed in the gastrointestinal tract. The maximum serum concentration is achieved 20 min after intravenous administration and 1-2 hours after oral administration. The bioavailability of metoprolol is of 100% when administered intravenously and when administered orally it presents about 50% for the tartrate derivative and 40% for the succinate derivative. The absorption of metoprolol in the form of the tartrate derivative is increased by the concomitant administration of food.
Metoprolol is mainly excreted via the kidneys. From the eliminated dose, less than 5% is recovered unchanged.
The reported volume of distribution of metoprolol is 4.2 L/kg. Due to the characteristics of metoprolol, this molecule is able to cross the blood-brain barrier and even 78% of the administered drug can be found in cerebrospinal fluid.
The reported clearance rate on patients with normal kidney function is 0.8 L/min. In cirrhotic patients, the clearance rate changes to 0.61 L/min.
Plasma levels following oral administration of conventional metoprolol tablets, however, approximate 50% of levels following intravenous adminsitration, indicating about 50% first-pass metabolism... Elimination is mainly by biotransformation in the liver.
Metoprolol tartrate is rapidly and almost completely absorbed from the GI tract; absorption of a single oral dose of 20-100 mg is complete in 2.5-3 hours. After an oral dose, about 50% of the drug administered as conventional tablets appears to undergo first-pass metabolism in the liver. Bioavailability of orally administered metoprolol tartrate increases with increased doses, indicating a possible saturable disposition process of low capacity such as tissue binding in the liver. Steady-state oral bioavailability of extended-release tablets of metoprolol succinate given once daily at dosages equivalent to 50-400 mg of metoprolol tartrate is about 77% of that of conventional tablets at corresponding dosages given once daily or in divided doses. Food does not appear to affect bioavailability of metoprolol succinate extended-release tablets. Following a single oral dose as conventional tablets, metoprolol appears in the plasma within 10 minutes and peak plasma concentrations are reached in about 90 minutes. When metoprolol tartrate conventional tablets are administered with food rather than on an empty stomach, peak plasma concentrations are higher and the extent of absorption of the drug is increased. Following oral administration of metoprolol succinate as extended-release tablets, peak plasma metoprolol concentrations are aobut 25-50% of those attained after administration of metoprolol tartrate conventional tablets given once daily or in divided doses. Time to peak concentration is longer with extended-release tablets, with peak plasma coentrations being reached in about 7 hours following administration of such tablets. Plasma concentrations attained 1 hour after an oral dose are linearly related to metoprolol tartrate doses ranging from 50-400 mg as conventional tablets.
Plasma metoprolol concentrations attained after iv administration of the drug are approximately 2 times those attained following oral administration. Following iv infusion of metoprolol over 10 minutes in healthy individuals, maximum beta-adrenergic blocking activity occurred at 20 minutes. In healthy individuals, a maximum reduction in exercise-induced heart rate of approximately 10 and 15% occurs following iv administration of a single 5 mg and 15 mg metoprolol dose, respectively; the effect on exercise-induced heart rate decreased linearly with time at the same rate for both doses and persisted for approximately 5 and 8 hours for the 5 mg and 15 mg doses, respectively.
Elimination of metoprolol appears to follow first-order kinetics and occurs mainly in the liver; the time required for the process apparently is independent of dose and duration of therapy. In healthy individuals and hypertensive patients, the elimination half-life of both unchanged drug and metabolites is about 3-4 hours. In poor hydroxylators of the drug, the elimination half-life is prolonged to about 7.6 hours. There is more interindividual variation in elimination half-lives in geriatric patients than in young healthy individuals. The half-life of metoprolol does not increase appreciably with impaired renal function.
For more Absorption, Distribution and Excretion (Complete) data for METOPROLOL (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
Metoprolol goes through significant first-pass hepatic metabolism which covers around 50% of the administered dose. The metabolism of metoprolol is mainly driven by the activity of CYP2D6 and to a lesser extent due to the activity of CYP3A4. The metabolism of metoprolol is mainly represented by reactions of hydroxylation and O-demethylation.
Metoprolol does not inhibit or enhance its own metabolism. Three main metabolites of the drug are formed by oxidative deamination, O-dealkylation with subsequent oxidation, and aliphatic hydroxylation; these metabolites account for 85% of the total urinary excretion of metabolites. The metabolites apparently do not have appreciable pharmacologic activity. The rate of hydroxylation, resulting in alpha-hydroxymetoprolol, is genetically determined and is subject to considerable interindividual variation. Poor hydroxylators of metoprolol have increased areas under the plasma concentration-time curves, prolonged elimination half-lives (about 7.6 hours), higher urinary concentrations of unchanged drug, and negligible urinary concentrations of alpha-hydroxymetoprolol compared with extensive hydroxylators. Beta-adrenergic blockade of exercise-induced tachycardia persists for at least 24 hours after administration of a single 200-mg oral dose of metoprolol tartrate in poor hydroxylators.
Controlled studies have shown that debrisoquine oxidation phenotype is a major determinant of the metabolism, pharmacokinetics and some of the pharmacological actions of metoprolol. The poor metabolizer phenotype is associated with increased plasma drug concentrations, a prolongation of elimination half-life and more intense and sustained beta blockade. Phenotypic differences have also been observed in the pharmacokinetics of the enantiomers of metoprolol. In vivo and in vitro studies have identified some of the metabolic pathways which are subject to the defect, that is alpha-hydroxylation and O-demethylation.
Metropolol is a racemic mixture of R-and S-enantiomers, and is primarily metabolized by CYP2D6.

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Biological Half-Life
The immediate release formulations of metoprolol present a half-life of about 3-7 hours.
The plasma half-life ranges from approximately 3 to 7 hours.

Hepatotoxicity
Metoprolol therapy has been associated with a low rate of mild-to-moderate elevations of serum aminotransferase levels which are usually asymptomatic and transient and resolve even with continuation of therapy. A few instances of clinically apparent, acute liver injury attributable to metoprolol have been reported. In view of its wide scale use, metoprolol induced liver injury is exceedingly rare. The typical liver injury associated with beta-blockers has a latency to onset of 2 to 12 weeks and a hepatocellular pattern of liver enzyme. Symptoms of hypersensitivity (rash, fever, eosinophilia) and autoantibody formation have not been reported. Reported cases due to metoprolol have included cases of acute liver failure, but ultimately all were self-limiting and resolved fairly rapidly once once drug was stopped.
Likelihood score: D (possible rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because of the low levels of metoprolol in breastmilk, amounts ingested by the infant are small and would not be expected to cause any adverse effects in breastfed infants. Studies on the use of metoprolol during breastfeeding have found no adverse reactions in breastfed infants. Monitor breastfed infants for symptoms of beta blockade such as bradycardia and listlessness due to hypoglycemia.
◉ Effects in Breastfed Infants
A study of mothers taking beta-blockers during nursing found a numerically, but not statistically significant increased number of adverse reactions in those taking any beta-blocker. Although the ages of infants were matched to control infants, the ages of the affected infants were not stated. Of 6 mothers taking metoprolol, none reported adverse effects in her breastfed infant.
◉ Effects on Lactation and Breastmilk
Relevant published information on the effects of beta-blockade or metoprolol during normal lactation was not found as of the revision date. A study in 6 patients with hyperprolactinemia and galactorrhea found no changes in serum prolactin levels following beta-adrenergic blockade with propranolol.
◈ What is metoprolol?
Metoprolol is a medication that has been used to treat high blood pressure, fast heart rate, and migraines. It is part of a class of medications known as beta-blockers. Some brand names for metoprolol are Lopressor®, Toprol®, Apo-Metoprolol®, Betaloc®, Novo-Metoprolol®, and Minimax®.Sometimes when people find out they are pregnant, they think about changing how they take their medication, or stopping their medication all together. However, it is important to talk with your healthcare providers before making any changes to how you take your medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy.
◈ I take metoprolol. Can it make it harder for me to get pregnant?
It is not known if taking metoprolol can make it harder to get pregnant.
◈ Does taking metoprolol increase the chance of miscarriage?
Miscarriage is common and can occur in any pregnancy for many different reasons. Studies have not been done to see if metoprolol can increase the chance of miscarriage.
◈ Does taking metoprolol increase the chance of birth defects?
Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. It is not known if metoprolol increases the chance of birth defects above the background risk. Animal studies have not reported an increased chance of birth defects. A study of a large number of pregnancies found that beta-blockers in general did not increase the chance of heart defects.
◈ Does taking metoprolol in pregnancy increase the chance of other pregnancy-related problems?
Metoprolol has been associated with reduced growth of the fetus. It is not clear if this happens because of the metoprolol, the health condition that is being treated, other factors, or a combination of factors. Metoprolol use in late pregnancy may cause the baby to have symptoms such as slowed heart rate and low blood sugar. Talk with your healthcare providers about your use of metoprolol so that if symptoms occur your baby can get the care that is best for them.
◈ Does taking metoprolol in pregnancy affect future behavior or learning for the child?
Studies have not been done to see if metoprolol can cause behavior or learning issues for the child.Breastfeeding while taking metoprolol:Metoprolol passes into breastmilk in small amounts. Studies on the use of metoprolol during breastfeeding have not reported side effects in breastfed infants. If you suspect the baby has any symptoms (such as slow heart rate, being too sleepy, having trouble with feeding, or pale skin), contact the child’s healthcare provider. Be sure to talk to your healthcare provider about all your breastfeeding questions.
◈ If a male takes metoprolol, could it affect fertility or increase the chance of birth defects?
It is not known if metoprolol could affect male fertility (ability to get partner pregnant) or increase the chance of birth defects above the background risk. In general, exposures that fathers or sperm donors have are unlikely to increase risks to a pregnancy. For more information, please see the MotherToBaby fact sheet on Paternal Exposures and Pregnancy at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

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Protein Binding
Metoprolol is not highly bound to plasma proteins and only about 11% of the administered dose is found bound. It is mainly bound to serum albumin.

[1]. Metoprolol reduces proinflammatory cytokines and atherosclerosis in ApoE-/- mice. Biomed Res Int. 2014;2014:548783.

[2]. Carvedilol has stronger anti-inflammation and anti-virus effects than metoprolol in murine model with coxsackievirus B3-induced viral myocarditis. Gene. 2014 Sep 1;547(2):195-201.

[3]. Cytotoxicity of Metoprolol on Leukemic Cells in Vitro. IJBC 2018; 10(4): 124-129.

[4]. Effect of metoprolol on myocardial apoptosis and caspase-9 activation after coronary microembolization in rats. Exp Clin Cardiol. 2013 Spring;18(2):161-5.

Metoprolol is a propanolamine that is 1-(propan-2-ylamino)propan-2-ol substituted by a 4-(2-methoxyethyl)phenoxy group at position 1. It has a role as a beta-adrenergic antagonist, an antihypertensive agent, a xenobiotic, an environmental contaminant and a geroprotector. It is a propanolamine, an aromatic ether, a secondary alcohol and a secondary amino compound.
Metoprolol is a selective beta-1 blocker commonly employed as the succinate and tartrate derivatives depending if the formulation is designed to be of immediate release or extended release. The possibility of the generation of these formulations comes from the lower systemic bioavailability of the succinate derivative. To this date, it is one of the preferred beta-blockers in general clinical guidelines and it is widely prescribed in the Netherlands, New Zealand, and the US. Metoprolol was developed since 1969 by US Pharmaceutical Holdings I and FDA approved in 1978.
Metoprolol is a beta-Adrenergic Blocker. The mechanism of action of metoprolol is as an Adrenergic beta-Antagonist.
Metoprolol is a cardioselective beta-blocker that is widely used in the treatment of hypertension and angina pectoris. Metoprolol has been linked to rare cases of drug induced liver injury.
Metoprolol has been reported in Carica papaya with data available.
Metoprolol is a cardioselective competitive beta-1 adrenergic receptor antagonist with antihypertensive properties and devoid of intrinsic sympathomimetic activity. Metoprolol antagonizes beta 1-adrenergic receptors in the myocardium, thereby reducing the rate and force of myocardial contraction leading to a reduction in cardiac output. This agent may also reduce the secretion of renin with subsequent reduction in levels of angiotensin II thereby preventing vasoconstriction and aldosterone secretion.
A selective adrenergic beta-1 blocking agent that is commonly used to treat ANGINA PECTORIS; HYPERTENSION; and CARDIAC ARRHYTHMIAS.
See also: Metoprolol Tartrate (has salt form); Metoprolol Succinate (has salt form); Metoprolol Fumarate (has salt form) ... View More ...

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Drug Indication
Metoprolol is indicated for the treatment of angina, heart failure, myocardial infarction, atrial fibrillation, atrial flutter and hypertension. Some off-label uses of metoprolol include supraventricular tachycardia and thyroid storm. All the indications of metoprolol are part of cardiovascular diseases. These conditions correspond to a number of diseases that involve the function of the heart and blood vessels. The underlying causes of these conditions are variable and can be due to genetic disposition, lifestyle decisions such as smoking, obesity, diet, and lack of exercise, and comorbidity with other conditions such as diabetes. The cardiovascular diseases are the leading cause of death on a global scale.
FDA Label

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Mechanism of Action
Metoprolol is a beta-1-adrenergic receptor inhibitor specific to cardiac cells with negligible effect on beta-2 receptors. This inhibition decreases cardiac output by producing negative chronotropic and inotropic effects without presenting activity towards membrane stabilization nor intrinsic sympathomimetics.
Beta-adenoreceptor blocking property the amount of beta1 and beta2 effect depends on the cardioselectivity of the drug. Decreased automaticity. Reduced conduction velocity and increased refractoriness in accessory bundles (Wolff- Parkinson-White syndrome). /Class II- beta-Blocking Agents/
At low doses, metoprolol is a selective inhibitor of beta 1-adrenergic receptors. Like propranolol, metoprolol inhibits response to adrenergic stimuli by competitively blocking b1-adrenergic receptors within the myocardium. Unlike propranolol, however, metoprolol blocks b2-adrenergic receptors within bronchial and vascular smooth muscle only in high doses.
The precise mechanism of metoprolol's hypotensive action has not been determined. It has been postulated that beta-adrenergic blocking agents reduce blood pressure by blocking peripheral (especially cardiac) adrenergic receptors (decreasing cardiac output), by decreasing sympathetic outflow from the CNS, and/or by suppressing renin release.
In the management of angina pectoris, the mechanism of action of metoprolol is thought to be blockage of catecholamine-induced increases in heart rate, velocity and extent of myocardial contraction, and blood pressure, which results in a net decrease in myocardial oxygen consumption.
For more Mechanism of Action (Complete) data for METOPROLOL (7 total), please visit the HSDB record page.

C15H25NO3

267.3639

267.183

C, 67.38; H, 9.43; N, 5.24; O, 17.95

51384-51-1

Metoprolol succinate;98418-47-4;Metoprolol-d7 hydrochloride;1219798-61-4;Metoprolol tartrate;56392-17-7;Metoprolol-d7;959787-96-3;(R)-Metoprolol-d7;1292907-84-6;(S)-Metoprolol-d7;1292906-91-2;Metoprolol-d5;959786-79-9; 51384-51-1; 56392-18-8 (HCl); 80274-67-5 (fumarate); 98418-47-4 (succinate)

4171

White to off-white solid

1.0±0.1 g/cm3

398.6±37.0 °C at 760 mmHg

194.9±26.5 °C

0.0±1.0 mmHg at 25°C

1.508

1.79

50.72

2

4

9

19

215

0

OC(CNC(C)C)COC1=CC=C(CCOC)C=C1

IUBSYMUCCVWXPE-UHFFFAOYSA-N

InChI=1S/C15H25NO3/c1-12(2)16-10-14(17)11-19-15-6-4-13(5-7-15)8-9-18-3/h4-7,12,14,16-17H,8-11H2,1-3H3

1-(isopropylamino)-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol

(RS)-Metoprolol; Beatrolol; dl-Metoprolol; 37350-58-6; Seroken; Spesicor;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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 (~374.03 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (9.35 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 (9.35 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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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。