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].

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/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.

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.

---

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.

---

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.

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.
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.
In contrast to early work showing inhibition of the absorption of beta adrenergic blocking drugs by antacids, subsequent studies did not confirm a reduction in the bioavailability of either atenolol or propranolol during antacid treatment; indeed, they showed an increase in the plasma concentrations of metoprolol when the drug was coadministered with an antacid.
Caffeine and metoprolol have been reported to increase peak salicylic acid concentration following aspirin administration.
For more Interactions (Complete) data for METOPROLOL (12 total), please visit the HSDB record page.

---

Non-Human Toxicity Values
LD50 Rat oral 3090-4670 mg/kg
LD50 Mice oral 1158-2460 mg/kg
LD50 Mouse female iv 118 mg/kg /Metoprolol tartrate/
LD50 Rat male iv ~90 mg/kg /Metoprolol tartrate/

[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.

Therapeutic Uses
Adrenergic beta-Antagonists; Anti-Arrhythmia Agents; Antihypertensive Agents; Sympatholytics
Metoprolol /is/ used in the treatment of mitral value prolapse syndrome. /NOT included in US product labeling/
Metoprolol ... /is/ used for thyrotoxicosis. /NOT included in US product labeling/
/Metoprolol has been used/ to control the physical manifestations of anxiety such as tachycardia and tremor. It is not particularly useful for chronic anxiety or panic attacks but is most useful for reducing anxiety and improving performance in specific stressful situations. /NOT included in US product labeling/
For more Therapeutic Uses (Complete) data for METOPROLOL (12 total), please visit the HSDB record page.

---

Drug Warnings
Tiredness or dizziness has occurred in about 10% of patients with hypertension or angina receiving metoprolol tartrate in clinical trials; tiredness has been reported in about 1% of patients with myocardial infarction receiving the drug. In addition, vertigo, sleep disturbances/insomnia, hallucinations, nightmares, headache, dizziness, visual disturbances, and confusion have been reported in patients with myocardial infarction receiving the drug, although a causal relationship is unclear. Somnolence or increased dreaming also has been reported with metoprolol therapy; these effects may be alleviated by avoiding late-evening dosing. rarely, impotence, nervousness, and general weakness have occurred. Depression has been reported in about 5% of patients receiving metoprolol tartrate for hypertension or angina. ... /Metoprolol tartrate/
Diarrhea has occurred in about 5% of patients receiving metoprolol tartrate in clinical trials. Other GI symptoms such as nausea, gastric pain, constipation, flatulence, digestive tract disorders, heartburn, xerostomia, and hiccups also have been reported with oral metoprolol therapy. Nausea and abdominal pain have occurred in less than 1% of patients with myocardial infarction receiving IV or oral metoprolol.
In 10 healthy subjects administration of metoprolol tartrate 50 mg by mouth increased the peripheral platelet count.
Peyronie's disease, tinnitus, restless legs, a polymyalgia-like syndrome, decreased libido, blurred vision, dry eyes, dry mucous membranes, agranulocytosis, and sweating have occurred rarely in patients receiving metoprolol. Pruritus, dry skin, worsening of psoriasis, and psoriasiform, maculopapular, and urticarial rash have occurred in some patients receiving metoprolol.
For more Drug Warnings (Complete) data for METOPROLOL (10 total), please visit the HSDB record page.

---

Pharmacodynamics
Administration of metoprolol in normal subjects is widely reported to produce a dose-dependent reduction on heart rate and cardiac output. This effect is generated due to a decreased cardiac excitability, cardiac output, and myocardial oxygen demand. In the case of arrhythmias, metoprolol produces its effect by reducing the slope of the pacemaker potential as well as suppressing the rate of atrioventricular conduction. The Metoprolol Atherosclerosis Prevention in Hypertensives (MAPHY) trial showed a significant improvement in sudden cardiac death and myocardial infarction when patients were given with metoprolol as compared with diuretics. As well, in clinical trials performed in 1990, metoprolol reduces mortality and re-infarction in 17% of the individuals when administered chronically after an episode of myocardial infarction.

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

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.35 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 2.5 mg/mL (9.35 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

---

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