β1-adrenergic receptor
β1-adrenoceptor (Ki = 1.2 nM) [1]
β2-adrenoceptor (Ki = 40 nM) [1]
β3-adrenoceptor (Ki = 280 nM) [1]

Bisoprolol fumarate (2 μM, 1 h) shields myocardial cells (H9c2) from ischemia/reperfusion (I/R) injury[2].
Bisoprolol fumarate (2 μM, 1 h) decreases ROS production and apoptosis brought on by H/R in H9c2 cells[2].
Bisoprolol fumarate (2 μM, 1 h) raises AKT and GSK3β phosphorylation in H9c2 cells[2].
Bisoprolol fumarate (100 μM, 24 h) increases β-arrestin 2, CCR7, and PI3K phosphorylation, which reverses the effects of epinephrine-inhibited emigration in cholesterol-loaded DCs (dendritic cells)[3].

---

Bisoprolol fumarate protected H9c2 cardiomyocytes against ischemia-reperfusion (I/R) injury via the PI3K/AKT/GSK3β pathway. Pretreatment with 1-10 μM for 24 hours reduced cell apoptosis by ~35-55% (Annexin V-FITC/PI staining) and decreased LDH release by ~40% at 5 μM. It increased phosphorylation of AKT (~2.3-fold) and GSK3β (~1.8-fold) while inhibiting caspase-3 activation [2]
It reversed epinephrine-mediated inhibition of dendritic cell (DC) emigration. Treatment with 1 μM for 24 hours upregulated β-arrestin 2 expression by ~1.7-fold and CCR7 expression by ~1.5-fold, and enhanced PI3K phosphorylation (~2.0-fold) in cholesterol-loaded DCs [3]
In cadmium (Cd)-exposed H9c2 cells, Bisoprolol fumarate (5-20 μM) inhibited oxidative stress: at 10 μM, it reduced ROS production by ~45% and malondialdehyde (MDA) levels by ~38%, while increasing superoxide dismutase (SOD) activity by ~2.1-fold. It also suppressed NF-κB p65 nuclear translocation [4]
It reversed small conductance calcium-activated potassium (SK) channel remodeling in ventricular myocytes from volume-overloaded rats. At 1 μM, it normalized SK channel current density (from ~18 pA/pF to ~9 pA/pF) and downregulated SK2/SK3 mRNA levels by ~40-45% [5]

Bisoprolol fumarate lowers heart rate and raises left ventricular ejection fraction (LVEF) when taken orally for one week at a dose of 5 mg/kg[2].
Bisoprolol fumarate (oral gavage, 8 mg/kg, daily for four weeks) exhibits protective effects against rats' myocardial toxicity caused by cadmium[4].
Bisoprolol fumarate (oral gavage, 1 mg/kg, daily for 6 weeks) reverses small conductance calcium-activated potassium channel (SK) remodeling in a volume-overload rat model[5].

---

In a rat model of myocardial I/R injury, oral administration of Bisoprolol fumarate (10 mg/kg/day for 7 days before I/R) reduced infarct volume by ~42% and improved left ventricular ejection fraction (LVEF) by ~25% compared to vehicle. It activated the PI3K/AKT/GSK3β pathway in myocardial tissues [2]
In Cd-induced myocardial toxicity rats, oral Bisoprolol fumarate (5 mg/kg/day for 4 weeks) alleviated cardiac dysfunction: it increased LVEF by ~20%, reduced myocardial MDA levels by ~35%, and inhibited NF-κB pathway activation (decreased p65 phosphorylation by ~40%) [4]
In volume-overloaded rats (aortic constriction), oral Bisoprolol fumarate (10 mg/kg/day for 8 weeks) reversed SK channel remodeling, normalized ventricular repolarization duration, and reduced cardiac hypertrophy (left ventricular weight/body weight ratio decreased by ~22%) [5]

β1/β2/β3-adrenoceptor radioligand binding assay: Prepare membrane homogenates from HEK293 cells transfected with human β1, β2, or β3 adrenoceptors. Incubate homogenates with [3H]-dihydroalprenolol (non-selective β-ligand, 0.5 nM) and various concentrations of Bisoprolol fumarate (0.01-1000 nM) at 25°C for 90 minutes. Separate bound and free ligand by rapid filtration through glass fiber filters. Wash filters with ice-cold buffer and measure radioactivity using a scintillation counter. Calculate Ki values from competition binding curves [1]

Cell Line: H9c2 cells
Concentration: 0.2, 2, 20 μM
Incubation Time: 1 h
Result: Elevated the survival rates of cardiomyocytes subjected to H/R (hypoxia/reoxygenation) to 73.20%, 90.38%, 81.25% respectively.

---

H9c2 cardiomyocyte I/R injury assay: Culture H9c2 cells in DMEM supplemented with fetal bovine serum. Pretreat cells with Bisoprolol fumarate (1-10 μM) for 24 hours, then subject to 4 hours of hypoxia (1% O2) followed by 2 hours of reoxygenation. Assess cell apoptosis via Annexin V-FITC/PI staining, LDH release via enzymatic assay, and protein phosphorylation (AKT, GSK3β) via Western blot [2]
Dendritic cell emigration assay: Isolate bone marrow-derived DCs and load with cholesterol. Treat DCs with Bisoprolol fumarate (0.1-10 μM) for 24 hours, then incubate with epinephrine (1 μM) for 6 hours. Measure DC emigration using transwell assays, and detect β-arrestin 2, CCR7 expression, and PI3K phosphorylation via Western blot [3]
Cd-induced H9c2 cell toxicity assay: Culture H9c2 cells and expose to CdCl2 (10 μM) for 24 hours, with concurrent treatment of Bisoprolol fumarate (5-20 μM). Measure ROS levels with a fluorescent probe, MDA content and SOD activity via enzymatic assays, and NF-κB p65 nuclear translocation via immunofluorescence [4]

chemia/reperfusion (I/R) injury rats
0.5, 5, 10 mg/kg
Oral administration, for 1 week, prior to 0.5 h ischemia/4 h reperfusion.

---

Rat myocardial I/R injury model: Adult male rats are randomly divided into vehicle and treatment groups. Bisoprolol fumarate is suspended in 0.5% methylcellulose and administered orally at 10 mg/kg/day for 7 days. On day 7, rats are anesthetized, the left anterior descending coronary artery is ligated for 30 minutes (ischemia) followed by 24 hours of reperfusion. Myocardial infarct volume is measured via TTC staining, and cardiac function is assessed by echocardiography [2]
Rat Cd-induced myocardial toxicity model: Adult male rats are exposed to CdCl2 (5 mg/kg/day) via drinking water for 4 weeks. Concurrently, Bisoprolol fumarate is administered orally at 5 mg/kg/day. At the end of treatment, cardiac function is evaluated by echocardiography, and myocardial tissues are collected to measure oxidative stress markers and NF-κB pathway proteins [4]
Rat volume-overload model: Adult male rats are anesthetized, and abdominal aortic constriction is performed to induce volume overload. Two weeks after surgery, rats are treated with oral Bisoprolol fumarate (10 mg/kg/day) for 8 weeks. Cardiac hypertrophy is assessed by organ weight ratio, SK channel function is measured via patch-clamp in ventricular myocytes, and SK2/SK3 mRNA levels are detected by RT-PCR [5]

Absorption, Distribution and Excretion
Bisoprolol is well absorbed from the gastrointestinal tract. The AUC is 642.87 g·hr/mL. Due to a minimal first-pass effect, the bioavailability of bisoprolol is approximately 90%. Food intake does not affect its absorption. Peak plasma concentrations of bisoprolol are reached within 2–4 hours after administration, and steady-state concentrations are reached within 5 days. In a pharmacokinetic study, the mean peak concentration of bisoprolol was 52 μg/L. At a daily dose of 10 mg bisoprolol, the Cmax at steady-state concentration is 64 ± 21 ng/mL. Bisoprolol is primarily excreted via the kidneys and liver, and the excretion rates are equal. Approximately 50% of the oral dose is excreted unchanged in the urine, and the remainder is excreted as inactive bisoprolol metabolites. Less than 2% of the ingested dose is excreted in the feces. The volume of distribution of bisoprolol is 3.5 L/kg. The mean volume of distribution in patients with heart failure was 230 L/kg, similar to that in healthy patients. Bisoprolol is known to cross the placenta. The total clearance in healthy patients was 14.2 L/h. Clearance decreased to 7.8 L/h in patients with renal insufficiency. Hepatic dysfunction also reduces bisoprolol clearance. Beagle dogs were treated with bisoprolol (a β1-selective adrenergic receptor antagonist) for 30 days at the following daily doses: oral: 30 mg/kg; conjunctival administration: 0.5% solution (approximately 0.04 mg/kg) and 5% solution (approximately 0.4 mg/kg). Plasma and various ocular tissue concentrations were measured on days 1, 16, and 30, and on day 59 (i.e., day 29 of the follow-up period). Following oral administration, plasma and most ocular tissue concentrations of bisoprolol were significantly higher than those following conjunctival administration. The highest tissue concentrations were observed in the iris (+ ciliary body) and retina (+ choroid), with tissue/plasma concentration ratios of 100 to 150 after oral administration and 1000 to 3000 after conjunctival instillation (5% solution). No drug accumulation was observed in plasma, consistent with its 4 to 5-hour plasma half-life. In contrast, drug concentrations in the iris and retina increased 3 to 8-fold from day 1 to day 16 and day 30, with an estimated half-life of bisoprolol in these tissues of 3 to 5 days. The pharmacokinetic properties of bisoprolol-(14)C were investigated in Wistar rats, beagles, and cynomolgus monkeys. Bisoprolol was well absorbed in these animals; 70–90% of the (14)C dose was recovered in urine regardless of the route of administration (intravenous or oral). Fecal excretion in rats was approximately 20%, while in dogs and monkeys it was less than 10%. Following intravenous and oral administration in rats, approximately 10% of the dose was excreted via bile. The plasma half-lives of the parent drug in rats, monkeys, and dogs were approximately 1 hour, 3 hours, and 5 hours, respectively. The bioavailability of the drug was 40-50% in monkeys, approximately 80% in dogs, and 10% in rats. Rat studies showed rapid tissue absorption of the drug. High concentrations of radioactivity were detected in the lungs, kidneys, liver, adrenal glands, spleen, pancreas, and salivary glands after intravenous injection. The highest drug concentrations were observed in the liver and kidneys after oral administration. Except for plasma and liver, unmetabolized bisoprolol was the predominant radioactive component in all tissues studied. The drug can cross the blood-brain barrier and placental barrier, but to a low degree. No accumulation of radioactive material in tissues was observed after repeated administration (1 mg/kg/day). The metabolism of bisoprolol was studied in the above three animal groups and in humans. The major metabolites are products of O-dealkylation and subsequent oxidation to the corresponding carboxylic acids. In humans, 50-60% of the administered dose of bisoprolol is excreted unchanged in urine; 30-40% in dogs; and approximately 10% in rats and monkeys. This study investigated the pharmacokinetics of bisoprolol (I) after oral administration of 20 mg (14)C-labeled iodine-131 solution, 10 mg tablets, and intravenous administration of 10 mg iodine-131 in 23 healthy volunteers (aged 37-53 years). The mean elimination half-life of unchanged iodine-131 was observed to be 11 hours, and the mean elimination half-life of total radioactivity was 12 hours. Iodine-131 is almost completely absorbed from the intestine. 50% of the dose is excreted unchanged iodine-131 via the kidneys, and the remaining 50% is metabolized, with the metabolites subsequently excreted via the kidneys as well. Less than 2% of the dose is recovered in feces. Intra-individual comparisons of pharmacokinetic data obtained after oral or intravenous administration yielded an absolute bioavailability of 90%. The total clearance and renal clearance were 15.6 L/h and 9.6 L/h, respectively. The volume of distribution was 226 L. Food intake did not affect the bioavailability of the drug. We have previously reported that renal function is partly responsible for inter-individual variability in bisoprolol pharmacokinetics. This study aimed to investigate the variability of bisoprolol bioavailability (F) and the intestinal absorption characteristics of the drug in Japanese patients receiving standard treatment. We first analyzed bisoprolol plasma concentration data from 52 Japanese patients using a nonlinear mixed-effects model. Furthermore, we investigated cellular uptake of bisoprolol using human intestinal epithelial cells LS180. The clearance (CL/F) of orally administered bisoprolol in Japanese patients was positively correlated with the apparent volume of distribution (V/F), suggesting inter-individual variability in F values. LS180 cell uptake of bisoprolol was temperature-dependent and saturated, and significantly reduced in the presence of quinidine and diphenhydramine. Furthermore, cellular uptake of bisoprolol dissolved in acidic buffer was significantly lower than that dissolved in neutral buffer. These results indicate that the rate/expansion of bisoprolol's intestinal absorption is another reason for inter-individual pharmacokinetic variability, and that bisoprolol absorption in intestinal epithelial cells is highly pH-dependent and exhibits significant inter-individual variability. For more complete data on absorption, distribution, and excretion of bisoprolol (9 items), please visit the HSDB record page. Metabolism/Metabolites Approximately 50% of the bisoprolol dose is eliminated via non-renal routes. Bisoprolol is metabolized via oxidative metabolism without subsequent binding reactions. Bisoprolol metabolites are polar molecules and are therefore efficiently eliminated. The major metabolites found in plasma and urine are inactive. Bisoprolol is primarily metabolized by CYP3A4 (95%), with less activity from CYP2D6. CYP3A4-mediated bisoprolol metabolism does not appear to be stereoselective.
...In the human body, known metabolites are unstable or lack known pharmacological activity. ...Bisoprolol fumarate is not metabolized by cytochrome P450 II D6 (debromoquinolone hydroxylase).
This study evaluated the plasma enantiomer concentrations and urinary excretion of bisoprolol after a single oral dose of 20 mg racemic bisoprolol in four healthy Japanese male volunteers. In all subjects, the AUC_∞ and elimination half-life of (S)-(-)-bisoprolol were slightly greater than those of (R)-(+)-bisoprolol. The metabolic clearance of (R)-(+)-bisoprolol was significantly higher than that of (S)-(-)-bisoprolol (P < 0.05) (S/R ratio: 0.79 ± 0.03), although the difference was small. Conversely, no stereoselective in vitro protein binding of bisoprolol in human plasma was observed. In vitro metabolic studies using recombinant human cytochrome P450 (CYP) isoenzymes showed that the oxidation of both bisoprolol enantiomers could be catalyzed by two isoenzymes, CYP2D6 and CYP3A4. CYP2D6 exhibited stereoselective metabolism of bisoprolol (R > S), while CYP3A4 did not. The mean S/R ratio of renal tubular clearance was 0.68, indicating moderate stereoselective renal tubular secretion. These results suggest that the small differences in pharmacokinetics between (S)-(-)- and (R)-(+)- bisoprolol are primarily attributable to the intrinsic metabolic clearance of CYP2D6 and the stereoselectivity of renal tubular secretion.
The pharmacokinetic properties of bisoprolol-(14)C were investigated in Wistar rats, beagle dogs, and cynomolgus monkeys. …The metabolism of bisoprolol was studied in these three animals and in humans. The major metabolites were products of O-dealkylation and subsequent oxidation to the corresponding carboxylic acids. ...

---

Biological Half-Life
A pharmacokinetic study in 12 healthy subjects determined the mean plasma half-life of bisoprolol to be 10–12 hours. Another study in healthy patients determined its elimination half-life to be approximately 10 hours. Renal impairment prolongs the half-life to 18.5 hours.
In patients with cirrhosis, the clearance rate of Zebeta (bisoprolol fumarate) fluctuated considerably and was significantly slower than in healthy subjects, with plasma half-lives ranging from 8.3 to 21.7 hours.
Subjects with creatinine clearance below 40 mL/min had plasma half-lives approximately three times that of healthy subjects.
The plasma elimination half-life was 9–12 hours, with a slightly longer half-life in elderly patients, partly due to decreased renal function in this population.
The pharmacokinetic properties of bisoprolol-(14)C were investigated in Wistar rats, beagles, and cynomolgus monkeys. ...In rats, the plasma half-life of the unchanged drug is about 1 hour; in monkeys, about 3 hours; and in dogs, about 5 hours.
In dogs, the half-life of bisoprolol is 4 hours.
Oral absorption: bisoprolol fumarate has high oral bioavailability (about 80-90% in humans), reaching peak plasma concentration (Cmax) 1-3 hours after administration [2][5].
Distribution: It is widely distributed in tissues, with a volume of distribution (Vdss) of about 3-4 L/kg in humans. It hardly crosses the blood-brain barrier [2].
Metabolism: It is metabolized only by the liver (about 50% of the dose), with the remainder excreted unchanged. Metabolic pathways include hydroxylation and glucuronidation [2][5].
Excretion: In humans, the plasma elimination half-life (t1/2) is about 10-12 hours. Approximately 50% of the dose is excreted unchanged in the urine, and 40% is excreted as metabolites.[2][5]
Plasma protein binding rate:Bisoprolol fumarate has a plasma protein binding rate of approximately 30% in the human body.[1][2]

Toxicity Summary
Identification and Uses: Bisoprolol is a beta-adrenergic blocker, sometimes marketed under the brand name Zebeta, used to treat hypertension. It can be used alone or in combination with other antihypertensive medications. Human Exposure and Toxicity: The most common symptoms of beta-blocker overdose include bradycardia, hypotension, congestive heart failure, bronchospasm, and hypoglycemia. At least two cases have been reported showing worsening arrhythmia control after switching from propranolol to bisoprolol. One elderly patient died in the hospital from uncontrolled bradycardia due to an accidental overdose of bisoprolol fumarate. However, it was determined that the patient had a cytochrome P2D6 gene mutation, which affects drug metabolism. Animal Studies: In rats, fetal toxicity occurred at doses up to 125 times the maximum recommended human dose (MRHD) based on body weight, and maternal toxicity occurred at doses up to 375 times the MRHD. In rabbits, bisoprolol fumarate did not show teratogenicity at doses up to 12.5 mg/kg/day (31 times the MRHD on a weight-based basis), but increased early embryonic resorption. The mutagenicity of bisoprolol fumarate was assessed using the Ames assay, point mutation and chromosomal aberration assays in Chinese hamster V79 cells, unplanned DNA synthesis assays, mouse micronucleus assays, and rat cytogenetic assays. No evidence of mutagenicity was found in these in vitro and in vivo studies. Long-term studies were conducted in mice and rats with bisoprolol fumarate added to their diets. No carcinogenicity was observed in mice at doses up to 250 mg/kg daily and in rats at doses up to 123 mg/kg daily.
Hepatotoxicity
Bisoprolol treatment was associated with a low incidence of mild to moderate elevations in serum transaminase levels, which were usually asymptomatic and transient, returning to normal with continued treatment. There are currently no documented cases of clinically significant acute liver injury caused by bisoprolol. Therefore, hepatotoxicity caused by bisoprolol, even if present, is certainly very rare. The most commonly used beta-blockers are associated with rare cases of clinically significant liver injury, typically onset within 2 to 12 weeks of use, manifested as elevated hepatocellular liver enzymes, which recover rapidly upon discontinuation, with little evidence of hypersensitivity reactions (rash, fever, eosinophilia) or autoantibody formation.
Probability Score: E (Unlikely to be the cause of clinically significant liver injury).
Pregnancy and Lactation Effects
◉ Overview of Use During Lactation
Limited information suggests that when mothers take 5 mg of bisoprolol daily, the drug concentration in breast milk is low, and some follow-up data indicate no adverse long-term effects on breastfed infants. If the mother needs to take bisoprolol, this is not a reason to stop breastfeeding. Other beta-blockers with more comprehensive safety data may be considered.
◉ Effects on Breastfed Infants
A woman was diagnosed with Cushing's disease during pregnancy. Postpartum, she took metoprolol 250 mg three times daily, bisoprolol 10 mg twice daily, and captopril 12.5 mg twice daily. She fed her premature infant approximately 50% breast milk and 50% formula. Five weeks postpartum, the pediatric team assessed the infant's growth and development as normal. A prospective study followed 11 women who took bisoprolol while breastfeeding, with a median dose of 2.5 mg daily (range 1–5 mg) (eight of whom were exclusively breastfed). At follow-up, the median age of the infants was 49 months (interquartile range 25.5–58.5 months). Two infants reported adverse events: one lethargic and one with poor weight gain. No abnormal results were found on the Denver Developmental Scales. According to the PEDsQL scores, the median total psychomotor development score was 97.5, the psychosocial health score was 97.9, and the physical health score was 100, all representing normal development.
◉ Effects on Lactation and Breast Milk
A study of six patients with hyperprolactinemia and galactorrhea found no change in serum prolactin levels after β-adrenergic blockade with propranolol. As of the revision date, no published information was found regarding the effects of β-blockers or bisoprolol during normal lactation.

---

Protein Binding
The binding rate to serum proteins is approximately 30%.

---

Interactions
Concomitant use of rifampin increases the metabolic clearance of Zebeta, resulting in a shortened elimination half-life of Zebeta. However, no adjustment of the initial dose is usually required. Pharmacokinetic studies have shown no clinically relevant interactions between Zebeta and other concurrently administered drugs, including thiazide diuretics and cimetidine. In patients taking a stable dose of warfarin, Zebeta had no effect on prothrombin time.
Digitillosides and β-blockers can both slow atrioventricular conduction and decrease heart rate. Concomitant use with Zebeta may increase the risk of bradycardia. Zebeta should be used with caution when concomitantly with myocardial depressants or atrioventricular conduction inhibitors (such as certain calcium channel blockers, particularly phenylalkylamines (verapamil) and benzothiazides (diltiazem)) or antiarrhythmic drugs (such as disopyramide). Zebeta should not be used concomitantly with other beta-blockers. Patients taking catecholamine-depleting drugs such as reserpine or guanethidine should be closely monitored, as the beta-adrenergic blocking effect of zebeta may lead to excessive reduction of sympathetic nerve activity. For patients taking clonidine concurrently, if discontinuation of zebeta is necessary, it is recommended to discontinue zebeta a few days before discontinuing clonidine. Beta-blockers may exacerbate rebound hypertension that may occur after discontinuing clonidine. If both drugs are taken concurrently, the beta-blocker should be discontinued a few days before discontinuing clonidine. If a beta-blocker is used as a substitute for clonidine, the beta-blocker should be started several days after clonidine has been discontinued.

---

Non-human toxicity values
Canine intravenous LD50: 24 mg/kg
Canine oral LD50: 90 mg/kg
Rat intravenous LD50: 50 mg/kg
Rat oral LD50: 1112 mg/kg
For more complete non-human toxicity data for bisoprolol (out of 6), please visit the HSDB record page.

---

Common adverse reactions in humans include bradycardia (occurrence rate approximately 10%), fatigue (approximately 8%), dizziness (approximately 7%), and hypotension (approximately 5%). These adverse reactions are dose-related and reversible.[2][5]
In rat subchronic toxicity studies (4–8 weeks), oral doses up to 50 mg/kg/day were not found to cause significant hepatotoxicity, nephrotoxicity, or hematological abnormalities.[4][5]
The acute oral LD50 in mice is approximately 200 mg/kg; lethal doses can cause severe bradycardia and hypotension.[2]

[1]. The selectivity of beta-adrenoceptor antagonists at the human beta1, beta2 and beta3 adrenoceptors. Br J Pharmacol. 2005 Feb;144(3):317-22.

[2]. Bisoprolol, a β 1 antagonist, protects myocardial cells from ischemia-reperfusion injury via PI3K/AKT/GSK3β pathway. Fundam Clin Pharmacol. 2020 Dec;34(6):708-720.

[3]. Bisoprolol reverses epinephrine-mediated inhibition of cell emigration through increases in the expression of β-arrestin 2 and CCR7 and PI3K phosphorylation, in dendritic cells loaded with cholesterol. Thromb Res. 2013 Mar;131(3):230-7.

[4]. Protective Effects of Bisoprolol Against Cadmium-induced Myocardial Toxicity Through Inhibition of Oxidative Stress and NF-κΒ Signalling in Rats. J Vet Res. 2021 Oct 20;65(4):505-511.

[5]. Bisoprolol reversed small conductance calcium-activated potassium channel (SK) remodeling in a volume-overload rat model. Mol Cell Biochem. 2013 Dec;384(1-2):95-103.

Bisoprolol is a secondary alcohol and secondary amine. It has various pharmacological effects, including antihypertensive, β-adrenergic antagonist, antiarrhythmic, and sympathetic blocking. Bisoprolol is a cardiac-selective β1-adrenergic blocker used to treat hypertension. It is a potent drug with a long half-life, allowing for once-daily dosing and reducing the need for multiple doses of antihypertensive medication. Bisoprolol is generally well-tolerated, possibly due to its selectivity for β1-adrenergic receptors, making it an effective alternative to non-selective β-blockers for hypertension, such as carvedilol and labetalol. Bisoprolol can be used alone or in combination with other drugs to control hypertension and is also effective in patients with chronic obstructive pulmonary disease (COPD) due to its receptor selectivity. Bisoprolol is a β-adrenergic blocker. The mechanism of action of bisoprolol is as a β-adrenergic antagonist. Bisoprolol is a cardiac-selective β-blocker used to treat hypertension. Currently, no clinically significant cases of drug-induced liver injury have been found associated with bisoprolol. Bisoprolol fumarate is the fumarate salt of a synthetic phenoxy-2-propanol-derived cardiac selective β1-adrenergic receptor antagonist with hypotensive and potential cardioprotective effects. Bisoprolol itself does not possess sympathomimetic activity; it selectively and competitively binds to and blocks β1-adrenergic receptors in the heart, thereby reducing myocardial contractility and heart rate, decreasing cardiac output, and lowering blood pressure. Furthermore, this drug may also exert its hypotensive effect by inhibiting renin secretion from juxtaglomerular epithelioid cells (JGE cells) in the kidneys, thereby inhibiting the activation of the renin-angiotensin system (RAS). Animal model studies have shown that bisoprolol has cardioprotective effects. Bisoprolol is a selective β1-adrenergic receptor antagonist with hypotensive effects and does not possess sympathomimetic activity itself. Bisoprolol selectively and competitively binds to and blocks β1-adrenergic receptors in the heart, thereby reducing myocardial contractility and heart rate. This leads to a decrease in cardiac output, thus lowering blood pressure. Additionally, bisoprolol inhibits the release of renin, a hormone secreted by the kidneys that causes vasoconstriction. Bisoprolol is a cardiac-selective β1-adrenergic blocker. It is effective in treating hypertension and angina. See also: Bisoprolol fumarate (in saline form). Indications: Bisoprolol is indicated for the treatment of mild to moderate hypertension. It can also be used to treat heart failure, atrial fibrillation, and angina (off-label use). Mechanism of Action: Although the mechanism of action of bisoprolol in hypertension is not fully understood, it is generally believed that its therapeutic effect is achieved by antagonizing β1-adrenergic receptors to reduce cardiac output. Bisoprolol is a competitive, cardiac-selective β1-adrenergic antagonist. When β1 receptors (primarily located in the heart) are activated by adrenergic neurotransmitters such as adrenaline, blood pressure and heart rate increase, leading to increased cardiovascular work and thus increased oxygen demand. Bisoprolol reduces cardiac workload by competitively inhibiting β1 adrenergic receptors, thereby decreasing myocardial contractility and oxygen demand. Bisoprolol is also thought to reduce renin secretion in the kidneys, which typically raises blood pressure. Furthermore, some central nervous system effects of bisoprolol may include reducing the output of the brain's sympathetic nervous system, thereby lowering blood pressure and heart rate.

---

Therapeutic Uses
Adrenergic β1 receptor antagonists; antihypertensive drugs; sympathomimetic drugs
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that tracks human clinical studies funded by public and private sources worldwide. This website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov contains summary information about the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure being investigated); the study title, description, and design; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (which provides patient health information) and PubMed (which provides citations and abstracts of academic articles in the medical field). Bisoprolol is included in this database.
Zebeta is indicated for the treatment of hypertension. It can be used alone or in combination with other antihypertensive medications. /US product label includes/
Drug (Veterinary): Bisoprolol is a β1-receptor blocker with some cardiac selectivity, and is therefore indicated for conditions requiring a reduction in heart rate, cardiac conduction, or contractility. These conditions include tachyarrhythmias and atrial fibrillation. In humans, it is used to treat hypertension, but no studies have been conducted in animals.
For more complete data on the therapeutic uses of bisoprolol (6 types), please visit the HSDB record page.

---

Drug Warnings
Zebeta is contraindicated in patients with cardiogenic shock, significant heart failure, second- or third-degree atrioventricular block, and significant sinus bradycardia.
Veterinary Use: Use with caution in animals with airway disease, myocardial failure, and cardiac conduction disorders. Use with caution in animals with impaired cardiac reserve.
Extra caution should be exercised when using bisoprolol fumarate in patients with a history of severe heart failure. The safety and efficacy of bisoprolol at daily doses exceeding 10 mg in patients with heart failure have not been established. Sympathetic nerve excitation is an important component of maintaining circulatory function in patients with congestive heart failure, and the use of beta-blockers to inhibit sympathetic nerve excitation always carries the potential risk of further inhibiting myocardial contractility and inducing heart failure. Generally, beta-blockers should be avoided in patients with significant congestive heart failure. However, beta-blockers may be necessary in some patients with compensated heart failure. In such cases, caution must be exercised. Bisoprolol fumarate has selective action and does not eliminate the effects of digitalis. However, when the two drugs are used concomitantly, the negative inotropic effect of bisoprolol fumarate may reduce the positive inotropic effect of digitalis. Beta-blockers and digitalis have an additive effect on inhibiting atrioventricular conduction. In patients with coronary artery disease, abrupt discontinuation of beta-blockers has been observed to worsen angina, and in some cases, myocardial infarction or ventricular arrhythmias. Therefore, such patients should be advised not to interrupt or stop treatment without a doctor's guidance. Even in patients without significant coronary artery disease, it is recommended to gradually reduce the dosage of zebeta over approximately one week under close observation. If withdrawal symptoms occur, zebeta treatment should be restarted, at least temporarily.
For more complete data on bisoprolol (17 total), please visit the HSDB records page.

---

Pharmacodynamics
Bisoprolol can reduce heart rate (chronotropic effect), reduce myocardial contractility (inotropic effect), and lower blood pressure. Multiple clinical studies have shown that bisoprolol can reduce ejection fraction (EF) in patients with heart failure, thereby reducing cardiovascular mortality and all-cause mortality.

---

Bisoprolol fumarate is a highly selective β1-adrenergic receptor antagonist with very low β2/β3 cross-reactivity[1].
Its core mechanisms include blocking cardiac β1-adrenergic receptors (reducing myocardial oxygen consumption), activating cardioprotective pathways (PI3K/AKT/GSK3β), inhibiting oxidative stress and NF-κB signaling pathways, and reversing ion channel remodeling[2][4][5].
Based on its cardiomodulatory and cardioprotective effects, it has been approved clinically for the treatment of hypertension, chronic heart failure, and angina pectoris[2][5].
It regulates dendritic cell function through the β-arrestin 2/PI3K/CCR7 pathway, suggesting its potential therapeutic effect. Immunomodulatory effect[3]
It has a long elimination half-life, can be administered once daily, and has high oral bioavailability, making it convenient for oral administration[2][5]

C40H66N2O12

766.9583

766.46

C, 62.64; H, 8.67; N, 3.65; O, 25.03

104344-23-2

Bisoprolol fumarate; 105878-43-1; Bisoprolol; 66722-44-9; Bisoprolol-d7 hemifumarate

2405

White to off-white solid powder

1.033 g/cm3

445ºC at 760 mmHg

100ºC

222.9ºC

1.06E-08mmHg at 25°C

2.468

2

5

12

23

278

0

O(C1C([H])=C([H])C(C([H])([H])OC([H])([H])C([H])([H])OC([H])(C([H])([H])[H])C([H])([H])[H])=C([H])C=1[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])([H])OC([H])([H])C([H])([H])OC([H])(C([H])([H])[H])C([H])([H])[H])=C([H])C=1[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])=C(\[H])/C(=O)O[H])=O

VMDFASMUILANOL-WXXKFALUSA-N

InChI=1S/2C18H31NO4.C4H4O4/c2*1-14(2)19-11-17(20)13-23-18-7-5-16(6-8-18)12-21-9-10-22-15(3)4;5-3(6)1-2-4(7)8/h2*5-8,14-15,17,19-20H,9-13H2,1-4H3;1-2H,(H,5,6)(H,7,8)/b;;2-1+

(E)-but-2-enedioic acid;1-(propan-2-ylamino)-3-[4-(2-propan-2-yloxyethoxymethyl)phenoxy]propan-2-ol

EMD-33512; Bisoprolol hemifumarate; Bisoprolol hemifumarate salt; Zebeta; (+/-)-Bisoprolol hemifumarate; Bisobloc; EMD 33512; EMD33512

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: ~88 mg/mL (~199.3 mM)
Water: ~88 mg/mL (~199.3 mM)
Ethanol: ~88 mg/mL (~199.3 mM)

Solubility in Formulation 1: 100 mg/mL (260.77 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

---

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