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.

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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
Metoprolol is almost completely absorbed from the gastrointestinal tract after oral administration. Peak plasma concentrations are reached 20 minutes after intravenous administration and 1–2 hours after oral administration. The bioavailability of metoprolol is 100% after intravenous administration, approximately 50% for tartaric acid derivatives, and approximately 40% for succinic acid derivatives after oral administration. Co-administration with food increases the absorption of metoprolol in the tartaric acid derivative form.
Metoprolol is primarily excreted via the kidneys. Less than 5% of the parent drug is recovered from the eliminated dose.
The reported volume of distribution of metoprolol is 4.2 L/kg. Due to its properties, metoprolol can cross the blood-brain barrier, with up to 78% of the administered drug detectable in cerebrospinal fluid.
The reported clearance rate in patients with normal renal function is 0.8 L/min. In patients with cirrhosis, the clearance rate becomes 0.61 L/min. However, plasma concentrations after oral administration of standard metoprolol tablets are 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. After oral administration, approximately 50% of the standard tablets appear to undergo first-pass metabolism in the liver. The bioavailability of oral metoprolol tartrate increases with increasing dose, suggesting the possible presence of low-volume saturation metabolic processes, such as binding to liver tissue. The steady-state oral bioavailability of metoprolol succinate extended-release tablets, equivalent to 50-400 mg of metoprolol tartrate once daily, is approximately 77% of that of the equivalent dose of once-daily or divided doses of standard tablets. Food does not appear to affect the bioavailability of metoprolol succinate extended-release tablets. Following a single oral dose of a regular tablet, metoprolol enters the plasma within 10 minutes and reaches peak plasma concentration in approximately 90 minutes. Compared to administration on an empty stomach, the peak plasma concentration is higher and the drug is more readily absorbed when taken with food. After oral administration of metoprolol succinate extended-release tablets, the peak plasma metoprolol concentration is approximately 25%–50% of the peak concentration achieved after once-daily or divided doses of regular metoprolol tartrate tablets. Extended-release tablets have a longer time to reach peak concentration, approximately 7 hours after administration. The plasma concentration reached 1 hour after oral administration of regular tablets (50–400 mg) is linearly related to the dose. After intravenous injection, the plasma metoprolol concentration is approximately twice that after oral administration. In healthy subjects, β-adrenergic blocking effect reaches its maximum at 20 minutes, 10 minutes after intravenous infusion of metoprolol. In healthy individuals, intravenous administration of a single dose of 5 mg and 15 mg metoprolol resulted in a maximum reduction in exercise-induced heart rate of approximately 10% and 15%, respectively. At both doses, the reduction in exercise-induced heart rate was linear over time at the same rate, with the reduction lasting approximately 5 hours and 8 hours, respectively, for the 5 mg and 15 mg doses. The 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 reduced drug hydroxylation capacity, the elimination half-life is prolonged to approximately 7.6 hours. Individual differences in the elimination half-life are greater in elderly patients than in younger, healthy individuals. The half-life of metoprolol is not significantly prolonged in patients with impaired renal function. For more complete data on the absorption, distribution, and excretion of metoprolol (7 types), please visit the HSDB records page.

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Metabolic/Metabolic Substances
Metoprolol undergoes significant first-pass hepatic metabolism, accounting for approximately 50% of the administered dose. Metoprolol metabolism is primarily driven by CYP2D6 activity, with less activity from CYP3A4. Metoprolol metabolism mainly 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; these metabolites account for 85% of the total urinary excretion of metabolites. These metabolites appear to have no significant pharmacological activity. The rate of hydroxylation to α-hydroxymetoprolol is determined by genetic factors and varies significantly between individuals. Compared to individuals with strong hydroxylation capacity, individuals with weak metoprolol hydroxylation capacity have 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 patients with impaired hydroxylation capacity, a single oral dose of 200 mg metoprolol tartrate resulted in β-adrenergic blockade of exercise-induced tachycardia lasting at least 24 hours. Controlled studies have shown that the norisoquinoline oxidation phenotype is a major determinant of metoprolol metabolism, pharmacokinetics, and some pharmacological effects. Impaired metabolic capacity is associated with higher plasma drug concentrations, prolonged elimination half-life, and more potent and prolonged β-blockade. Furthermore, phenotypic differences have been observed in the pharmacokinetics of metoprolol enantiomers. In vivo and in vitro studies have identified several defect-affected metabolic pathways, namely α-hydroxylation and O-demethylation. Metoprolol is a racemic mixture of R- and S-enantiomers, primarily metabolized by CYP2D6. The half-life of immediate-release metoprolol formulations is approximately 3–7 hours. The plasma half-life is approximately 3 to 7 hours.

Interactions
This study investigated the effect of verapamil co-administration on the hepatic first-pass clearance of metoprolol in dogs. Deuterium-labeled pseudoracemic metoprolol was administered via single intravenous injection (0.51 mg/kg) and oral administration (1.37 mg/kg), with concurrent or non-concurrent administration of racemic verapamil (3 mg/kg). Plasma concentration-time curves of metoprolol enantiomers and urinary recovery of oxidized metabolites were measured. Verapamil inhibited approximately 50-70% of the systemic and oral clearance of metoprolol. The first-pass effect of metoprolol completely disappeared after verapamil co-administration, indicating a significant reduction in hepatic clearance from moderate to low levels. In control dogs, hepatic clearance of metoprolol showed slight (S)-enantiomer selectivity (R/S ratio 0.89 ± 0.04). Verapamil's inhibitory effect on metoprolol hepatic clearance is selectively directed against (S)-metoprolol; therefore, enantioselectivity of hepatic clearance for (S)-metoprolol disappears upon concomitant administration of verapamil (R/S ratio 1.01 ± 0.05). Urinary metabolite profiles indicate that O-demethylation and N-dealkylation are the major oxidative metabolic pathways in dogs. α-Hydroxymetoprolol is a minor metabolite in urine. N-dealkylation shows a strong preference for (S)-metoprolol, while O-demethylation and α-hydroxylation show moderate selectivity for (R)-metoprolol. Therefore, there is a slight (S)-enantioselectivity in overall hepatic clearance. Comparison of metoprolol metabolite formation and clearance with and without verapamil showed that all three oxidative pathways were inhibited by 60-80%. Compared to (R)-metoprolol, (S)-metoprolol exhibited stronger inhibition of hepatic clearance, attributed to the significant (S)-enantioselective inhibition of metoprolol O-demethylation by verapamil. The interaction of metoprolol with bromazepam and lorazepam was investigated in 12 healthy male volunteers aged 21–37 years. Metoprolol had no significant effect on the pharmacokinetics of either bromazepam or lorazepam. However, the area under the curve (AUC) of 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 had no effect on other tests. Within the dose range used in this study, lorazepam (2 mg) was more potent than bromazepam (6 mg). Interactions between metoprolol and bromazepam and lorazepam are unlikely to be clinically significant. No dose change is necessary when using these drugs in combination. Contrary to earlier studies suggesting that antacids inhibit the absorption of β-adrenergic blockers, subsequent studies have not confirmed that antacid treatment reduces the bioavailability of atenolol or propranolol; in fact, plasma concentrations of metoprolol do increase when used in combination with antacids. Caffeine and metoprolol have been reported to increase peak salicylic acid concentrations after aspirin administration. For more complete data on metoprolol interactions (12 in total), please visit the HSDB records page.

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Non-human toxicity values
Oral LD50 in rats: 3090-4670 mg/kg
Oral LD50 in mice: 1158-2460 mg/kg
Intravenous LD50 in female mice: 118 mg/kg (metoprolol tartrate)
Intravenous LD50 in male rats: Approximately 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-blockers; antiarrhythmics; antihypertensives; sympathomimetic agents.
Metoprolol is used to treat mitral valve prolapse syndrome. (Not included on the US product label)
Metoprolol…is used to treat thyrotoxicosis. (Not included on the US product label)
Metoprolol has been used to control the physical manifestations of anxiety, such as tachycardia and tremor. It is not significantly effective for chronic anxiety or panic attacks, but is best suited for reducing anxiety and improving performance in specific stressful situations. /Not included on the US product label/
For more complete data on the therapeutic uses of metoprolol (12 types), please visit the HSDB record page.

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Drug Warnings
In clinical trials, approximately 10% of patients with hypertension or angina experienced fatigue or dizziness after taking metoprolol tartrate; approximately 1% of patients with myocardial infarction reported fatigue after taking this drug. In addition, dizziness, sleep disturbances/insomnia, hallucinations, nightmares, headaches, lightheadedness, visual disturbances, and confusion have been reported in patients with myocardial infarction taking this drug, but the causal relationship is unclear. Drowsiness or vivid dreams have also been reported with metoprolol treatment; avoiding taking the medication late at night can alleviate these side effects. In rare cases, impotence, nervousness, and general weakness may occur. Approximately 5% of patients taking metoprolol tartrate for hypertension or angina have been reported to experience depressive symptoms. .../Metoprolol Tartrate/
In clinical trials, approximately 5% of patients taking metoprolol tartrate experienced diarrhea. Oral metoprolol treatment may also cause other gastrointestinal symptoms such as nausea, stomach pain, constipation, flatulence, gastrointestinal disturbances, heartburn, dry mouth, and hiccups. The incidence of nausea and abdominal pain is less than 1% in patients with myocardial infarction receiving intravenous or oral metoprolol treatment.
In 10 healthy subjects, oral administration of 50 mg metoprolol tartrate increased peripheral blood platelet count.
Rare adverse reactions observed in patients receiving metoprolol included Peroni's disease, tinnitus, restless legs syndrome, polymyalgia-like syndrome, decreased libido, blurred vision, dry eyes, dry mucous membranes, agranulocytosis, and hyperhidrosis. Some patients taking metoprolol experienced pruritus, dry skin, exacerbation of psoriasis, and psoriasis-like rashes, maculopapular rashes, and urticarial rashes.
For more complete data on drug warnings for metoprolol (10 in total), please visit the HSDB record page.
Pharmacodynamics

It has been reported that in normal subjects, administration of metoprolol produces a dose-dependent decrease in heart rate and cardiac output. This effect is due to a decrease in cardiac excitability, cardiac output, and myocardial oxygen consumption. For arrhythmias, metoprolol works by reducing the slope of the pacing potential and inhibiting atrioventricular conduction velocity. The MAPHY trial of metoprolol for the prevention of atherosclerosis in hypertensive patients showed that, compared with diuretics, patients taking metoprolol had a significantly lower risk of sudden death and myocardial infarction. Furthermore, in a clinical trial conducted in 1990, long-term use of metoprolol after a myocardial infarction reduced mortality and re-infarction rates by 17%.

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.

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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.

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