β1 adrenoceptor

Metoprolol (0-1000 μg/mL; 24-72 h) exhibits dose- and time-dependent cytotoxicity on MOLT-4 and U937 cells[3].

Metoprolol (2.5 mg/kg/h; infusion; 11 weeks) decreases atherosclerosis and proinflammatory cytokines in ApoE-/- mice[1].
Metoprolol (15 mg/kg/q12h; i.e., 5 days) exhibits anti-viral and anti-inflammatory properties in a murine model of viral myocarditis caused by the coxsackievirus B3[2].
Metoprolol (2.5 mg/kg; intravenously; three bolus injections) inhibits myocardial apoptosis and significantly reduces the expression of activated caspase-9 protein in coronary microembolization (CME) rats[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

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.

Effects During Pregnancy and Lactation
◉ Overview of Medication 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 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 infants' ages were matched to 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.
A prospective study of pregnant women taking beta-blockers asked mothers to complete a questionnaire about postpartum breastfeeding and any side effects on their breastfed infants. Two mothers reported taking metoprolol while breastfeeding, but did not report the specific dosage. Neither reported any 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 breastfeeding. A study of six patients with hyperprolactinemia and galactorrhea found no change in serum prolactin levels after beta-adrenergic blockade with propranolol.

[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 succinate is an alcohol compound belonging to the phenolic class of compounds. Metoprolol succinate is the succinate form of metoprolol, a cardiac selective competitive β1-adrenergic receptor antagonist with antihypertensive effects and no intrinsic sympathomimetic activity. Metoprolol succinate antagonizes β1-adrenergic receptors in the myocardium, thereby reducing the frequency and intensity of myocardial contractions, and consequently reducing cardiac output. This drug may also reduce renin secretion, thereby lowering angiotensin II levels, thus reducing sympathetic activation, including vasoconstriction and aldosterone secretion. It is a commonly used selective β1-adrenergic blocker used to treat angina pectoris and hypertension, as well as arrhythmias. See also: metoprolol (active fraction); hydrochlorothiazide; metoprolol succinate (component).

C34H56N2O10

652.8159

652.393

C, 62.55; H, 8.65; N, 4.29; O, 24.51

98418-47-4

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)

62937

White to off-white solid powder

398.6ºC at 760 mmHg

194.9ºC

3.944

6

12

21

46

308

0

O(C1C([H])=C([H])C(=C([H])C=1[H])C([H])([H])C([H])([H])OC([H])([H])[H])C([H])([H])C([H])(C([H])([H])N([H])C([H])(C([H])([H])[H])C([H])([H])[H])O[H].O(C1C([H])=C([H])C(=C([H])C=1[H])C([H])([H])C([H])([H])OC([H])([H])[H])C([H])([H])C([H])(C([H])([H])N([H])C([H])(C([H])([H])[H])C([H])([H])[H])O[H].O([H])C(C([H])([H])C([H])([H])C(=O)O[H])=O

RGHAZVBIOOEVQX-UHFFFAOYSA-N

InChI=1S/2C15H25NO3.C4H6O4/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;1-2H2,(H,5,6)(H,7,8)

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

Metoprolol succinate; Dutoprol; Selozok; Toprol XL; Seloken-ZOK; H 93/26 succinate; Spesicor Dos; H 93/26 succinate; Toprol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 16.7~100 mg/mL (25.5~153.2 mM)
Water: ~100 mg/mL
Ethanol: ~5 mg/mL

Solubility in Formulation 1: ≥ 1.67 mg/mL (2.56 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 16.7 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: ≥ 1.67 mg/mL (2.56 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 16.7 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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Solubility in Formulation 3: ≥ 1.67 mg/mL (2.56 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 16.7 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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