| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
β1 adrenoceptor
The primary molecular target of Metoprolol fumarate is the beta-1 adrenergic receptor (ADRB1). It acts as a competitive antagonist, blocking the effects of catecholamines on beta-1 receptors. This reduces heart rate, contractility, and cardiac output, lowering blood pressure and myocardial oxygen demand. |
|---|---|
| ln Vitro |
Metoprolol (0-1000 μg/mL; 24-72 hours) cytotoxic effects on MOLT-4 and U937 cells are dose- and time-dependent [3].
In vitro, Metoprolol fumarate binds with high affinity to beta-1 adrenergic receptors. It demonstrates selectivity for beta-1 over beta-2 receptors. The compound inhibits catecholamine-induced increases in heart rate and contractility in isolated cardiac preparations. |
| 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].
In vivo, Metoprolol fumarate reduces heart rate and blood pressure in animal models and humans. It is used for the treatment of hypertension, angina, and heart failure. The compound improves survival in patients with heart failure and reduces the risk of myocardial infarction. |
| Enzyme Assay |
For beta-1 adrenergic receptor binding assays, membranes from cells expressing recombinant beta-1 receptors or cardiac tissue are incubated with [125I]iodocyanopindolol and increasing concentrations of Metoprolol fumarate. Nonspecific binding is determined with excess unlabeled ligand.
|
| 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). For in vitro functional assays, isolated cardiac myocytes or papillary muscles are treated with Metoprolol fumarate, and the effect on catecholamine-induced increases in contractility is measured. IC50 values are determined from dose-response curves. |
| 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. For in vivo studies, hypertensive rats or dogs receive Metoprolol fumarate by oral or intravenous administration. Heart rate and blood pressure are measured. Clinical studies evaluate its efficacy in hypertension, angina, and heart failure. |
| ADME/Pharmacokinetics |
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. 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. 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. |
