| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
Metoprolol Fumarate (Lanoc; Selopral; Ritmolol; Metomerck; Metop; Toprol; Lopressor), the Fumarate salt of Metoprolol, is a potent β1 adrenergic receptor blocker approved for use as an anti-hypertensive medication for the treatment of high blood pressure and chest pain.
| Targets |
β1 adrenoceptor
|
|---|---|
| ln Vitro |
Metoprolol (0-1000 μg/mL; 24-72 hours) cytotoxic effects on MOLT-4 and U937 cells are dose- and time-dependent [3].
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| ln Vivo |
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 Assay |
Cytotoxicity assay [3]
Cell Types: U937 and MOLT-4 Cell Tested Concentrations: 1, 10, 50, 100, 500 and 1000 μg/mL Incubation Duration: 24, 48 and 72 hrs (hours) Experimental Results: Dramatically diminished viability of U937 and MOLT -4 Cells incubated at a concentration of 1000 μg/mL (3740.14μM) for 48 hrs (hours) Dramatically diminished the viability of U937 cells after incubation at a concentration of ≥500 μg/ml (≥1870.07μM) for 72 hrs (hours), and Dramatically diminished the viability of U937 cells after incubation for 72 hrs (hours). hrs (hours) later, MOLT4 cell concentration was ≥100 μg/ml (≥374.01μM). |
| Animal Protocol |
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. 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. |
| ADME/Pharmacokinetics |
Absorption
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. Route of Elimination Metoprolol is mainly excreted via the kidneys. From the eliminated dose, less than 5% is recovered unchanged. Volume of Distribution 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. Clearance 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. View More
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.
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. PMID:2868819 Metropolol is a racemic mixture of R-and S-enantiomers, and is primarily metabolized by CYP2D6. 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. |
| Toxicity/Toxicokinetics |
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). 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. View More
◈ What is metoprolol?
Interactions The effect of verapamil coadministration on the hepatic first pass clearance of metoprolol was investigated in dogs. Plasma concentration-time course of metoprolol enantiomers and urinary recovery of oxidative metabolites were determined after a single iv (0.51 mg/kg) and an oral (1.37 mg/kg) dose of deuterium labeled pseudoracemic metoprolol, with or without concomitant administration of racemic verapamil (3 mg/kg). Verapamil inhibited both the systemic and oral clearance of metoprolol by about 50-70%. The first pass effect of metoprolol was completely abolished after coadministration of verapamil, reflecting a marked alteration in the degree of hepatic extraction of metoprolol from intermediate to low. The hepatic clearance of metoprolol was slightly (S)-enantioselective (R/S ratio = 0.89 + or - 0.04) in control dogs. Inhibition of hepatic clearance of metoprolol by verapamil was selective towards (S)-metoprolol, such that the enantioselectivity in hepatic clearance toward (S)-metoprolol disappeared following verapamil coadministration (R/S ratio = 1.01 + or - 0.05). Urinary metabolite profiles indicated that O-demethylation and N-dealkylation were the major pathways of oxidative metabolism in the dog. alpha-Hydroxymetoprolol was a minor metabolite in urine. N-Dealkylation showed a strong preference for (S)-metoprolol, whereas O-demethylation and alpha-hydroxylation exhibited a modest selectivity toward (R)-metoprolol; hence, the slight (S)-enantioselectivity in the overall hepatic clearance. Comparison of metoprolol metabolite formation clearances in the absence or presence of verapamil coadministration showed that all three oxidative pathways were inhibited by 60-80%. The greater inhibition of hepatic clearance observed with (S)-metoprolol as compared to (R)-metoprolol was attributed to a significant (S)-enantioselective inhibition in the O-demethylation of metoprolol by verapamil. PMID:1687016 The interaction between metoprolol and bromazepam and lorazepam was studied in 12 healthy male volunteers aged 21-37 years. Metoprolol had no significant effect on the pharmacokinetics of bromazepam or lorazepam. However, bromazepam area under the curve was 35% higher in the presence of metoprolol. Bromazepam enhanced the effect of metoprolol on systolic blood pressure but not on diastolic blood pressure or pulse rate. Lorazepam had no effect on either blood pressure or pulse. Metoprolol did not enhance the effect of bromazepam on the psychomotor tests used in this study. Metoprolol caused a small increase in critical flicker fusion threshold with lorazepam but had no effect on the other tests. Lorazepam (2 mg) was more potent than bromazepam (6 mg) in the doses used in this study. The interaction of metoprolol with bromazepam and lorazepam is unlikely to be of clinical significance. No change in dose is necessary when using these drugs together. 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. |
| References | |
| Additional Infomation |
Metoprolol Fumarate is the fumarate salt form of metoprolol, 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, and consequently a diminished 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.
See also: Metoprolol (has active moiety). |
| Molecular Formula |
2[C15H25NO3].C4H4O4
|
|---|---|
| Molecular Weight |
650.79996
|
| Exact Mass |
383.194
|
| Elemental Analysis |
C, 62.75; H, 8.36; N, 4.30; O, 24.58
|
| CAS # |
80274-67-5
|
| Related CAS # |
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)
|
| PubChem CID |
6440651
|
| Appearance |
Typically exists as solid at room temperature
|
| Hydrogen Bond Donor Count |
6
|
| Hydrogen Bond Acceptor Count |
12
|
| Rotatable Bond Count |
20
|
| Heavy Atom Count |
46
|
| Complexity |
334
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
COCCC1C=CC(OCC(CNC(C)C)O)=CC=1.COCCC1C=CC(OCC(CNC(C)C)O)=CC=1.OC(=O)/C=C/C(=O)O
|
| InChi Key |
BRIPGNJWPCKDQZ-WXXKFALUSA-N
|
| InChi Code |
InChI=1S/2C15H25NO3.C4H4O4/c2*1-12(2)16-10-14(17)11-19-15-6-4-13(5-7-15)8-9-18-3;5-3(6)1-2-4(7)8/h2*4-7,12,14,16-17H,8-11H2,1-3H3;1-2H,(H,5,6)(H,7,8)/b;;2-1+
|
| Chemical Name |
(E)-but-2-enedioic acid;1-[4-(2-methoxyethyl)phenoxy]-3-(propan-2-ylamino)propan-2-ol
|
| Synonyms |
Metoprolol fumarate; 80274-67-5; Lopresor OROS; CGP 2175C; Lopressor ORO; UNII-IO1C09Z674; 119637-66-0; LOPRESSOR OROS;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
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
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|---|---|
| Solubility (In Vivo) |
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.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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). View More
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)] Oral Formulations
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). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5366 mL | 7.6829 mL | 15.3657 mL | |
| 5 mM | 0.3073 mL | 1.5366 mL | 3.0731 mL | |
| 10 mM | 0.1537 mL | 0.7683 mL | 1.5366 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02123056 | Active Recruiting |
Drug: Metoprolol Drug: Matching Placebo |
Vasovagal Syncope | University of Calgary | October 2014 | Phase 4 |
| NCT01608893 | Active Recruiting |
Drug: Carvedilol Drug: Metoprolol |
Atrial Fibrillation | University of Calgary | May 2012 | Not Applicable |
| NCT03278509 | Active Recruiting |
Drug: Metoprolol Succinate Drug: Bisoprolol |
Acute Myocardial InfarctionST Elevation Myocardial Infarction |
Karolinska Institutet | September 11, 2017 | Phase 4 |
| NCT03070184 | Active Recruiting |
Other: Exercise challenge Drug: Metoprolol Succinate ER |
Healthy Pre Hypertension |
University of Alabama at Birmingham |
April 30, 2017 | Phase 2 |
| NCT05741385 | Recruiting | Drug: Caffeine Drug: Warfarin sodium Drug: Omeprazole Drug: Metoprolol |
Liver Cirrhosis | Boehringer Ingelheim | April 25, 2023 | Not Applicable |
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