β1 adrenoceptor

Metoprolol (0-1000 μg/mL; 24-72 hours) cytotoxic effects on MOLT-4 and U937 cells are dose- and time-dependent [3].

In ApoE−/− mice, metoprolol (2.5 mg/kg/h; infusion; 11 weeks) decreases atherosclerosis and pro-inflammatory cytokines [1]. Metoprolol (15 mg/kg/q12h; ig; 5 days) demonstrated antiviral and anti-inflammatory properties in a mouse model of viral myocarditis caused by the coxsackievirus B3 [2]. In rats with coronary microembolism (CME), metoprolol (2.5 mg/kg; intravenous injection; 3 bolus injections) effectively prevented cardiomyocyte death and reduced activated caspase-9 protein expression [4].

Cell Line: U937 and MOLT-4 cells
Concentration: 1, 10, 50, 100, 500 and 1000 μg/mL
Incubation Time: 24, 48 and 72 h
Result: Significantly reduced the viability of MOLT-4 and U937 cells at 1000 μg/mL (3740.14µM) concentration after 48 hours of incubation; similarly, after 72 hours, the viability of MOLT4 cells at ≥100 μg/ml (≥374.01µM) concentrations and U937 cells at ≥500 μg/ml (≥1870.07µM) concentrations was observed.

Male ApoE^-/- mice
2.5 mg/kg/h
Via osmotic minipumps, 11 weeks

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A total of 116 Balb/c mice were included in this study. Ninety-six mice were inoculated intraperitoneally with CVB3 to induce VMC. The CVB3 inoculated mice were evenly divided into myocarditis group (n=32), carvedilol group (n=32) and metoprolol group (n=32). Twenty mice (control group) were inoculated intraperitoneally with normal saline. Hematoxylin and eosin staining and histopathologic scoring were used to investigate the effects of carvedilol and metoprolol on myocardial histopathologic changes on days 3 and 5. In addition, serum cTn-I levels, cytokine levels and virus titers were determined using chemiluminescence immunoassay, enzyme-linked immunosorbent assay and plaque assay, respectively, on days 3 and 5. Finally, the levels of phosphorylated p38MAPK were studied using immunohistochemical staining and Western blotting on day 5.[2]

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Forty rats were randomly divided into four groups (n=10 each): a sham operation (control) group, CME plus saline (CME) group, CME plus metoprolol (metoprolol) group and caspase-9 inhibitor Z-LEHD-FMK (ZLF) group. CME was induced by injecting 3000 polyethylene microspheres (42 μm diameter) into the left ventricle during a 10 s occlusion of the ascending aorta. Echocardiography, terminal deoxynucleotidyl transferase dUTP nick end labelling and Western blotting were used to evaluate cardiac function, apoptosis and activation of caspase-9/caspase-3, respectively, 6 h after CME.[3]

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A few studies in animals and humans suggest that metoprolol (β1-selective adrenoceptor antagonist) may have a direct antiatherosclerotic effect. However, the mechanism behind this protective effect has not been established. The aim of the present study was to evaluate the effect of metoprolol on development of atherosclerosis in ApoE(-/-) mice and investigate its effect on the release of proinflammatory cytokines. Male ApoE(-/-) mice were treated with metoprolol (2.5 mg/kg/h) or saline for 11 weeks via osmotic minipumps. Atherosclerosis was assessed in thoracic aorta and aortic root. Total cholesterol levels and Th1/Th2 cytokines were analyzed in serum and macrophage content in lesions by immunohistochemistry. Metoprolol significantly reduced atherosclerotic plaque area in thoracic aorta (P < 0.05 versus Control). Further, metoprolol reduced serum TNFα and the chemokine CXCL1 (P < 0.01 versus Control for both) as well as decreasing the macrophage content in the plaques (P < 0.01 versus Control). Total cholesterol levels were not affected. In this study we found that a moderate dose of metoprolol significantly reduced atherosclerotic plaque area in thoracic aorta of ApoE(-/-) mice. Metoprolol also decreased serum levels of proinflammatory cytokines TNFα and CXCL1 and macrophage content in the plaques, showing that metoprolol has an anti-inflammatory effect.[1]

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Absorption
After oral administration, metoprolol is almost completely absorbed by the gastrointestinal tract. Peak plasma concentration is reached 20 minutes after intravenous administration and 1-2 hours after oral administration. The bioavailability of metoprolol via intravenous injection is 100%, while the bioavailability of metoprolol tartrate is approximately 50% and that of metoprolol succinate is approximately 40% upon oral administration. Co-administration with food increases the absorption of metoprolol tartrate.
Excretion
Metoprolol is primarily excreted via the kidneys. Less than 5% of the excreted drug is recovered unchanged.
Volume of Distribution
The volume of distribution of metoprolol is reported to be 4.2 L/kg. Due to its properties, metoprolol can cross the blood-brain barrier, and up to 78% of the administered drug can be detected in cerebrospinal fluid.
Clearance
The clearance rate in patients with normal renal function is reported to be 0.8 L/min. In patients with cirrhosis, clearance became 0.61 L/min. However, plasma concentrations after oral administration of standard metoprolol tablets were approximately 50% of those after intravenous administration, indicating that about 50% of the drug undergoes first-pass metabolism… The drug is primarily eliminated via hepatic biotransformation. Metoprolol tartrate is rapidly and almost completely absorbed from the gastrointestinal tract; after a single oral dose of 20–100 mg, it is completely absorbed within 2.5–3 hours. Following oral administration, approximately 50% of the drug in standard tablets appears to undergo first-pass metabolism in the liver. The bioavailability of metoprolol tartrate increases with increasing dose, suggesting the possible presence of low-volume saturation processes, such as liver tissue binding. A once-daily dose of metoprolol succinate extended-release tablets, equivalent to 50-400 mg of metoprolol tartrate, provides approximately 77% of the steady-state oral bioavailability of the equivalent dose of conventional tablets taken once or in divided doses. Food does not appear to affect the bioavailability of metoprolol succinate extended-release tablets. After a single oral dose of a conventional tablet, metoprolol enters the plasma within 10 minutes and reaches peak plasma concentration in approximately 90 minutes. Compared to fasting, conventional metoprolol tartrate tablets, when taken with food, result in higher peak plasma concentrations and greater drug absorption. After oral administration of metoprolol succinate extended-release tablets, the peak plasma metoprolol concentration is approximately 25%–50% of the peak concentration achieved with once-daily or divided doses of conventional metoprolol tartrate tablets. The extended-release tablets have a longer time to peak concentration, reaching peak plasma concentration approximately 7 hours after administration. Plasma concentrations reached 1 hour after oral administration of 50–400 mg metoprolol tartrate tablets are linearly related to the dose. Plasma metoprolol concentrations reached after intravenous injection are approximately twice that after oral administration. In healthy individuals, β-adrenergic blocking activity reaches its maximum at 20 minutes, 10 minutes after intravenous infusion of metoprolol. In healthy individuals, the maximum reduction in exercise-induced heart rate after a single intravenous injection of 5 mg and 15 mg metoprolol were approximately 10% and 15%, respectively; at both doses, the reduction in exercise-induced heart rate decreased linearly over time at the same rate, and the duration of action at 5 mg and 15 mg doses was approximately 5 hours and 8 hours, respectively. Elimination of metoprolol appears to follow first-order kinetics, primarily in the liver; the time required for elimination appears to be independent of dose and duration of treatment. In healthy individuals and hypertensive patients, the elimination half-life of the parent drug and its metabolites is approximately 3–4 hours. In patients with weaker hydroxylating capacity, the elimination half-life is prolonged to approximately 7.6 hours. Individual variability in the elimination half-life is greater in elderly patients than in younger, healthy individuals. Impaired renal function does not significantly prolong the half-life of metoprolol.

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Metabolism/Metabolites
Metoprolol is primarily metabolized via first-pass metabolism in the liver, accounting for approximately 50% of the administered dose. Metoprolol metabolism is mainly driven by CYP2D6, with lower activity in CYP3A4. The metabolism of metoprolol primarily involves hydroxylation and O-demethylation.
Metoprolol does not inhibit or enhance its own metabolism. The three main metabolites of this drug are formed by oxidative deamination, oxidation following O-dealkylation, and aliphatic hydroxylation, respectively; these metabolites account for 85% of the total metabolites in urine. The metabolites appear to have no significant pharmacological activity. The rate of hydroxylation to α-hydroxymetoprolol is genetically determined and varies significantly between individuals. Compared to individuals with high hydroxylation capacity, individuals with low metoprolol hydroxylation capacity exhibited a larger area under the plasma concentration-time curve, a prolonged elimination half-life (approximately 7.6 hours), higher urinary concentrations of the parent drug, and extremely low urinary concentrations of α-hydroxymetoprolol. In individuals with low hydroxylation capacity, the effect of a single oral dose of 200 mg metoprolol tartrate on exercise-induced tachycardia persisted for at least 24 hours. Controlled studies have shown that the norisoquinoline oxidation phenotype is a major factor determining metoprolol metabolism, pharmacokinetics, and some pharmacological effects. Poor metabolism phenotypes are associated with higher plasma drug concentrations, prolonged elimination half-life, and more potent and prolonged β-receptor blocking effects. Phenotypic differences have also been observed in the pharmacokinetics of metoprolol enantiomers. In vivo and in vitro studies have identified several metabolic pathways affected by metabolic defects, namely α-hydroxylation and O-demethylation. PMID: 2868819
Metoprolol is a racemic mixture of R- and S-enantiomers, primarily metabolized by CYP2D6.

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Biological Half-Life
The half-life of immediate-release metoprolol is approximately 3-7 hours.
The plasma half-life is approximately 3 to 7 hours.

Hepatotoxicity
Metoprolol treatment is associated with a low incidence of mild to moderate elevations in serum transaminase levels, which are usually asymptomatic and transient, and return to normal with continued treatment. A few clinically significant cases of metoprolol-related acute liver injury have been reported. Given the widespread use of metoprolol, liver injury caused by it is extremely rare. The typical latency period for beta-blocker-related liver injury is 2 to 12 weeks, with hepatocellular enzymes. There have been no reports of hypersensitivity symptoms (rash, fever, eosinophilia) or autoantibody formation. Reported cases of metoprolol-induced liver failure include acute liver failure, but all cases were ultimately self-limiting, with symptoms rapidly resolving after discontinuation of the drug.
Probability Score: D (Possibly a rare cause of clinically significant liver injury).
Effects during Pregnancy and Lactation◉ Overview of Use During Lactation
Because the concentration of metoprolol in breast milk is low and the amount ingested by the infant is small, no adverse effects are expected on breastfed infants. Studies on metoprolol use during breastfeeding have not found any adverse reactions in breastfed infants. Breastfed infants should be monitored for symptoms caused by beta-blockers, such as bradycardia and drowsiness due to hypoglycemia.
◉ Effects on Breastfed Infants
A study of mothers taking beta-blockers during lactation found a numerically increased number of adverse reactions in mothers taking any beta-blocker, but this was not statistically significant. Although the ages of the affected infants were matched with those in the control group, the ages of the affected infants were not specified. None of the six mothers taking metoprolol reported adverse reactions in their breastfed infants.
◉ Effects on Lactation and Breast Milk
As of the revision date, no published information was found regarding the effects of beta-blockers or metoprolol during normal lactation. A study of six patients with hyperprolactinemia and galactorrhea found no change in serum prolactin levels after beta-adrenergic blockade with propranolol.

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◈ What is Metoprolol?
Metoprolol is a medication used to treat high blood pressure, tachycardia, and migraines. It belongs to the beta-blocker class of drugs. Some brand names for metoprolol include Lopressor®, Toprol®, Apo-Metoprolol®, Betaloc®, Novo-Metoprolol®, and Minimax®. Sometimes, when people find out they are pregnant, they may consider changing how they take their medication or even stopping it altogether. However, it is essential to consult your healthcare provider before changing how you take your medication. Your healthcare provider can discuss with you the benefits of treating your condition and the risks of not treating it during pregnancy.
◈ I am taking metoprolol. Will it affect my ability to get pregnant?
It is currently unclear whether taking metoprolol affects pregnancy.
◈ Does taking metoprolol increase the risk of miscarriage?
Miscarriage is common and can occur in any pregnancy for a variety of reasons. There is currently no research indicating that metoprolol increases the risk of miscarriage.
◈ Does taking metoprolol increase the risk of birth defects?
There is a 3-5% risk of birth defects in each pregnancy, known as background risk. It is currently unclear whether metoprolol increases the risk of birth defects on top of the background risk. Animal studies have not found an increased risk of birth defects. A study of a large number of pregnancies found that beta-blockers generally do not increase the risk of fetal heart defects.
◈ Does taking metoprolol during pregnancy increase the risk of other pregnancy-related problems?
Metoprolol has been associated with fetal growth restriction. It is currently unclear whether this is due to metoprolol itself, the disease it treats, other factors, or a combination of factors. Taking metoprolol in late pregnancy may cause symptoms such as slowed heart rate and hypoglycemia in the fetus. Discuss your use of metoprolol with your healthcare provider so that your baby can receive optimal care if symptoms occur.
◈ Will taking metoprolol during pregnancy affect my child's future behavior or learning?
There is currently no research indicating whether metoprolol causes behavioral or learning problems in children. Breastfeeding while taking metoprolol: A small amount of metoprolol passes into breast milk. Studies on metoprolol use during breastfeeding have not reported side effects in breastfed infants. If you suspect your baby has any symptoms (such as slow heart rate, lethargy, feeding difficulties, or pale skin), contact your baby's healthcare provider. Be sure to consult your healthcare provider about all breastfeeding-related questions.
◈ If a man takes metoprolol, will it affect his fertility or increase the risk of birth defects?
It is currently unclear whether metoprolol affects male fertility (the ability to impregnate a partner) or increases the risk of birth defects (above background risk). Generally, contact with the father or sperm donor is unlikely to increase the risk of pregnancy. For more information, please refer to the MotherToBaby website's information sheet on paternal exposure and pregnancy: https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

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Interactions
The effect of verapamil concomitant administration on the hepatic first-pass clearance of metoprolol was studied in dogs. Plasma concentration-time curves of metoprolol enantiomers and urinary recovery of oxidized metabolites were determined after a single intravenous (0.51 mg/kg) and oral (1.37 mg/kg) administration of deuterium-labeled pseudoracemic metoprolol, with or without concurrent administration of racemic verapamil (3 mg/kg). Verapamil inhibited the systemic and oral clearance of metoprolol by approximately 50–70%. With concomitant administration of verapamil, the first-pass effect of metoprolol completely disappeared, indicating a significant reduction in hepatic extraction of metoprolol from moderate to low levels. In control dogs, metoprolol exhibited slight (S)-enantioselectivity in liver clearance (R/S ratio 0.89 ± 0.04). Verapamil selectively inhibited metoprolol liver clearance, particularly (S)-metoprolol. With verapamil in combination, the liver clearance selectivity for (S)-metoprolol disappeared (R/S ratio 1.01 ± 0.05). Urinary metabolite profiling revealed O-demethylation and N-dealkylation as the major oxidative metabolic pathways in dogs. α-Hydroxymetoprolol was present in low concentrations in urine. N-dealkylation showed a strong preference for (S)-metoprolol, while O-demethylation and α-hydroxylation exhibited lower selectivity for (R)-metoprolol; therefore, the enantioselectivity of (S)-metoprolol in overall liver clearance was weak. Comparison of metoprolol metabolite formation and clearance with and without verapamil showed that all three oxidative pathways were inhibited by 60-80%. (S)-metoprolol exhibited stronger inhibition of hepatic clearance compared to (R)-metoprolol, attributed to the significant (S)-enantioselective inhibition of metoprolol O-demethylation by verapamil. PMID:1687016
This study investigated the interaction of metoprolol with bromazepam and lorazepam in 12 healthy male volunteers aged 21-37 years. Results showed that metoprolol had no significant effect on the pharmacokinetics of bromazepam or lorazepam. However, the area under the curve (AUC) for bromazepam increased by 35% in the presence of metoprolol. Bromazepam enhanced the effect of metoprolol on systolic blood pressure but had no effect on diastolic blood pressure or pulse rate. Lorazepam had no effect on blood pressure or pulse rate. Metoprolol did not enhance the effect of bromazepam on the psychomotor tests used in this study. When metoprolol was used in combination with lorazepam, the critical scintillation fusion threshold was slightly increased, but other tests were unaffected. Within the dose range used in this study, lorazepam (2 mg) was more potent than bromazepam (6 mg). The interaction between metoprolol and bromazepam and lorazepam is unlikely to be clinically significant. No dose change is necessary when using these drugs in combination.

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Protein Binding
Metoprolol has a low binding rate to plasma proteins, with only about 11% of the administered dose binding to plasma proteins. It primarily binds to serum albumin.

[1]. Ulleryd MA, et al. Metoprolol reduces proinflammatory cytokines and atherosclerosis in ApoE-/- mice. Biomed Res Int. 2014;2014:548783.
[2]. Wang D, et al. 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]. Hajatbeigi B, et al. Cytotoxicity of Metoprolol on Leukemic Cells in Vitro. IJBC 2018; 10(4): 124-129.
[4]. Su Q, et al. 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 drug with the structure 1-(propan-2-ylamino)propan-2-ol, substituted at position 1 with 4-(2-methoxyethyl)phenoxy. It has multiple functions, including as a β-adrenergic antagonist, antihypertensive drug, exogenous substance, environmental pollutant, and anti-aging agent. It is a propanolamine compound, aromatic ether compound, secondary alcohol compound, and secondary amino compound. Metoprolol is a selective β1-receptor blocker, typically used in the form of succinate and tartrate derivatives, depending on whether the formulation is designed for immediate or sustained release. These formulations were developed due to the lower systemic bioavailability of succinate derivatives. To date, it remains one of the first-line β-receptor blockers recommended in clinical guidelines and is widely used in the Netherlands, New Zealand, and the United States. Metoprolol was developed by US Pharmaceutical Holdings I starting in 1969 and received FDA approval in 1978. Metoprolol is a beta-adrenergic blocker. Its mechanism of action is as a beta-adrenergic antagonist. According to the FDA drug classification, metoprolol is a cardiac-selective beta-blocker widely used to treat hypertension and angina. Metoprolol has been associated with rare cases of drug-induced liver injury.

C15H25NO3.HCL

303.82484

303.16

C, 59.30; H, 8.63; Cl, 11.67; N, 4.61; O, 15.80

56392-18-8

51384-51-1;56392-17-7 (tartrate);56392-18-8 (HCl); 80274-67-5 (fumarate); Metoprolol succinate; 98418-47-4; Metoprolol-d7 hydrochloride; 1219798-61-4; Metoprolol-d6 tartrate; 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

3043945

Typically exists as solid at room temperature

398.6ºC at 760 mmHg

194.9ºC

2.806

3

4

9

20

215

0

CC(C)NCC(COC1=CC=C(C=C1)CCOC)O.Cl

UKBBZNRSHOCRNP-UHFFFAOYSA-N

InChI=1S/C15H25NO3.ClH/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;1H

1-[4-(2-methoxyethyl)phenoxy]-3-(propan-2-ylamino)propan-2-ol;hydrochloride

Metoprolol hydrochloride; 56392-18-8; Metoprolol HCl; AS4SUC4LC5; 1-[4-(2-methoxyethyl)phenoxy]-3-(propan-2-ylamino)propan-2-ol hydrochloride; Lopressor, Betaloc, CGP-2175, H 93-26; 1-[4-(2-methoxyethyl)phenoxy]-3-(propan-2-ylamino)propan-2-ol;hydrochloride; UNII-AS4SUC4LC5; (+-)-1-(4-(2-Methoxyethyl)phenoxy)-3-((1-methylethyl)amino)-2-propanol hydrochloride;

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)