β-adrenoceptor

In vitro activity: Sotalol hydrochloride is a strong and non-specific β-adrenergic receptor antagonist. With an IC50 value of about 1.2 mM in HEK cell lines, sotalol is also a potassium channel inhibitor.

One antiarrhythmic medication is sotalol.Up to 100 mg/kg of sotalol has no effect on the electroconvulsive threshold. Sotalol does not interfere with the antielectroshock effects of lamotrigine, pregabalin, topiramate, or oxcarbazepine when administered at doses of 80–100 mg/kg. Neither long-term memory nor motor function are hampered by sotalol, either by alone or in combination with antiepileptic medications. Lamotrigine's brain concentration is greatly reduced by sotalol (100 mg/kg), but topiramate's and oxcarbazepine's are increased. Pregabalin levels are unaffected[3].

Class II antiarrhythmics or β-blockers are antisympathetic nervous system agents that act by blocking β-adrenoceptors. Despite their common clinical use, little is known about the effects of β-blockers on free intracellular calcium (Ca2+ i), an important cytosolic second messenger and a key regulator of cell function. We investigated the role of four chemical analogs, commonly prescribed β-blockers (atenolol, metoprolol, propranolol, and sotalol), on Ca2+ i release and whole-cell currents in mammalian cancer cells (PC3 prostate cancer and MCF7 breast cancer cell lines). We discovered that only propranolol activated free Ca2+ i release with distinct kinetics, whereas atenolol, metoprolol, and sotalol did not. The propranolol-induced Ca2+ i release was significantly inhibited by the chelation of extracellular calcium with ethylene glycol tetraacetic acid (EGTA) and by dantrolene, an inhibitor of the endoplasmic reticulum (ER) ryanodine receptor channels, and it was completely abolished by 2-aminoethoxydiphenyl borate, an inhibitor of the ER inositol-1,4,5-trisphosphate (IP3) receptor channels. Exhaustion of ER stores with 4-chloro-m-cresol, a ryanodine receptor activator, or thapsigargin, a sarco/ER Ca2+ ATPase inhibitor, precluded the propranolol-induced Ca2+ i release. Finally, preincubation of cells with sotalol or timolol, nonselective blockers of β-adrenoceptors, also reduced the Ca2+ i release activated by propranolol. Our results show that different β-blockers have differential effects on whole-cell currents and free Ca2+ i release and that propranolol activates store-operated Ca2+ i release via a mechanism that involves calcium-induced calcium release and putative downstream transducers such as IP3 The differential action of class II antiarrhythmics on Ca2+ i release may have implications on the pharmacology of these drugs[1].

Animal/Disease Models: 20-25 g female Swiss mice[3]
Doses: 100 mg/kg
Route of Administration: Administered intraperitoneally (ip)
Experimental Results: Dramatically diminished the brain concentrations of Lamotrigine and increased those of Oxcarbazepine and Topiramate.

Absorption, Distribution and Excretion
Sotalol has a bioavailability of 90-100%. Absorption is reduced by 18% when taken with food. The maximum concentration is 6.25 ± 2.19 mL/min in patients with creatinine clearance >80 mL/min. 80-90% of the administered dose is excreted unchanged in the urine. A small amount is excreted unchanged in the feces. The apparent volume of distribution is 1.2-2.4 L/kg. In patients with creatinine clearance >80 mL/min, the plasma clearance is 6.78 ± 2.72 L/h, and the renal clearance is 4.99 ± 1.43 L/h. In patients with creatinine clearance 30-80 mL/min, the plasma clearance is 2.74 ± 0.53 L/h, and the renal clearance is 2.00 ± 0.67 L/h. For patients with creatinine clearance of 10-30 mL/min, plasma clearance was 1.56 ± 0.44 L/h, and renal clearance was 0.65 ± 0.31 L/h. For patients with creatinine clearance <10 mL/min, plasma clearance was 0.65 ± 0.20 L/h, and renal clearance was 0.27 ± 0.13 L/h. Metabolism/Metabolites: Sotalol is not metabolized. Biological Half-Life: The terminal elimination half-life in healthy patients is 10-20 hours. For patients with creatinine clearance >80 mL/min, the half-life was 17.5 ± 0.97 h; for patients with creatinine clearance 30-80 mL/min, the half-life was 22.7 ± 6.4 h; for patients with creatinine clearance 10-30 mL/min, the half-life was 64 ± 27.2 h; and for patients with creatinine clearance <10 mL/min, the half-life was 97.9 ± 57.3 h.

Hepatotoxicity
In patients taking sotalol, the incidence of mild to moderate elevations in serum transaminase levels is less than 2%, usually transient and asymptomatic, and returns to normal with continued treatment. Sotalol has been associated with one case of clinically significant liver injury in a patient who developed acute hepatitis-like syndrome with persistent jaundice 12 weeks after starting sotalol. The liver injury improved but did not completely resolve after discontinuation of sotalol. Sotalol was not listed as a cause in a large series of drug-induced liver disease and acute liver failure cases. Other beta-blockers have been associated with rare cases of clinically significant liver injury with a latency period of 4 to 24 weeks, hepatocellular elevations in serum enzymes, mild and spontaneous course, and no evidence of hypersensitivity or autoimmune reactions. Probability score: E (Unlikely to be the cause of clinically significant liver injury).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
Because sotalol is largely secreted into breast milk and primarily excreted through the kidneys, other beta-blockers should be preferred over sotalol, especially in breastfeeding newborns or preterm infants. Some authors suggest that infants should be closely monitored for beta-blocking responses when using sotalol during lactation. Infant exposure is expected to decrease after 4 weeks of age or later.
◉ Effects on breastfed infants
A study of mothers taking beta-blockers while breastfeeding found a numerically increased number of adverse events 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. One of the mothers was taking sotalol.
A 12-day-old infant who was breastfed from birth did not experience bradycardia while a mother was taking 600 mg of sotalol daily. In another case, a breastfed infant whose mother took 80 mg daily, 2-3 times a day, for more than 3 months, did not exhibit bradycardia, and all developmental milestones were achieved normally. Beta-adrenergic blockers with similar milk excretion characteristics and renal clearance have had adverse effects on breastfed newborns. ◉ Effects on lactation and breast milk As of the revision date, no published information was found regarding the effects of beta-blockers or sotalol during normal lactation. A study of 6 patients with hyperprolactinemia and galactorrhea found no change in serum prolactin levels after beta-adrenergic blockade with propranolol.

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Protein binding
0%.

[1]. Marta Reyes-Corral, et al. Differential Free Intracellular Calcium Release by Class II Antiarrhythmics in Cancer Cell Lines. J Pharmacol Exp Ther. 2019 Apr;369(1):152-162.
[2]. Xiaomei Li, et al. Pediatric Dosing of Intravenous Sotalol Based on Body Surface Area in Patients with Arrhythmia. Pediatr Cardiol. 2017 Oct;38(7):1450-1455.
[3]. Kinga K Borowicz-Reutt, et al. Sotalol does not interfere with the antielectroshock action of selected second-generation antiepileptic drugs in mice.Pharmacol Rep. 2021 Apr;73(2):516-524.

Sotalol is a sulfonamide compound with the structure N-phenylmethanesulfonamide, where the phenyl group is substituted at the 4-position with a 1-hydroxy-2-(isopropylamino)ethyl group. It has antiarrhythmic effects by blocking β-adrenergic receptors (Vaughan Williams class II) and prolonging the duration of myocardial action potentials (Vaughan Williams class III). It is used (usually in hydrochloride form) to treat ventricular and supraventricular arrhythmias. It is a β-adrenergic antagonist, antiarrhythmic drug, environmental pollutant, and exogenous substance. It belongs to the ethanolamine, secondary amino, secondary alcohol, and sulfonamide classes. It is the conjugate base of sotalol (1+). Sotalol is a methanesulfonylaniline compound developed in 1960. It was the first class III antiarrhythmic drug. Sotalol was first approved for marketing on October 30, 1992, in oral tablet form. Currently, racemic mixtures of sotalol are formulated as tablets, oral solutions, and intravenous injections for the treatment of life-threatening ventricular arrhythmias and for maintaining normal sinus rhythm in atrial fibrillation or atrial flutter. Sotalol is an antiarrhythmic drug. Its mechanism of action is as a β-adrenergic receptor antagonist. The physiological effects of sotalol are achieved by altering heart rhythm. Sotalol is a non-selective β-adrenergic blocker primarily used to treat arrhythmias. Sotalol has been associated with at least one clinically significant case of liver injury. Sotalol is an ethanolamine derivative with class III antiarrhythmic and antihypertensive properties. Sotalol is a non-selective β-adrenergic receptor and potassium channel antagonist. In the heart, this drug inhibits positive chronotropic and positive inotropic effects, thereby slowing the heart rate and reducing myocardial contractility. This drug also reduces sinus rate, slows conduction velocity in the atria and atrioventricular node, and prolongs the functional refractory period of the atrioventricular node.
A beta-blocker used to treat life-threatening arrhythmias.
See also: Sotalol hydrochloride (salt form).
Drug Indications

Sophalol is indicated for the treatment of life-threatening ventricular arrhythmias and for maintaining normal sinus rhythm in patients with atrial fibrillation or atrial flutter. Oral solutions and intravenous injections are also available for patients who require sotalol but are not suitable for tablets.
FDA Label
Mechanism of Action

Sophalol inhibits β1-adrenergic receptors and fast potassium channels in the myocardium, thereby slowing repolarization, prolonging the QT interval, and slowing and shortening action potential conduction in the atria. The action of sotalol on β-adrenergic receptors prolongs the sinoatrial node cycle, atrioventricular node conduction time, refractory period, and action potential duration.

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Pharmacodynamics
Sotalol is a competitive inhibitor of fast potassium channels. This inhibition prolongs the duration and refractory period of the action potential in the atria and ventricles. The inhibition of fast potassium channels increases with decreasing heart rate, thus making adverse reactions such as torsades de pointes more likely at lower heart rates. Levosotalol also has β-adrenergic receptor blocking activity at plasma concentrations above 800 ng/L. Sotalol's β-receptor blocking effect further prolongs the action potential. Dextrosotalol does not have β-receptor blocking activity but can still reduce heart rate during standing or exercise. These effects collectively produce a negative inotropic effect, reducing the contractility of cardiomyocytes. QT interval prolongation is also associated with an increased risk of arrhythmias. Patients with non-insulin-dependent diabetes mellitus have a higher risk of hyperglycemia than those with insulin-dependent diabetes mellitus. β-blockers inhibit insulin secretion, which may lead to hyperglycemia in patients with type 2 diabetes mellitus. Patients with insulin-dependent diabetes mellitus have a higher risk of hypoglycemia than those with non-insulin-dependent diabetes mellitus. Beta-blockers reduce insulin secretion, which may mask hypoglycemia symptoms in insulin-dependent patients. Beta-blockers also increase cellular glucose uptake, which may prolong or worsen hypoglycemia. For more information on adverse reactions, please click here.

C12H20N2O3S

272.3638

272.119

3930-20-9

Sotalol hydrochloride;959-24-0;Sotalol-d6;1246912-17-3

5253

Typically exists as solid at room temperature

1.239 g/cm3

443.3ºC at 760 mmHg

221.9ºC

1.57

2.634

3

5

6

18

330

0

CS(=O)(NC1=CC=C(C(O)CNC(C)C)C=C1)=O

ZBMZVLHSJCTVON-UHFFFAOYSA-N

InChI=1S/C12H20N2O3S/c1-9(2)13-8-12(15)10-4-6-11(7-5-10)14-18(3,16)17/h4-7,9,12-15H,8H2,1-3H3

N-[4-[1-hydroxy-2-(propan-2-ylamino)ethyl]phenyl]methanesulfonamide

beta-Cardone; DL-Sotalol; Sotalolum; Darob mite; Sotalolum [INN-Latin]; N-(4-(1-Hydroxy-2-(isopropylamino)ethyl)phenyl)methanesulfonamide;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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