β1 adrenoceptor
β1-adrenoceptor (Ki = 0.3 nM) [2]
β2-adrenoceptor (Ki = 30 nM) [2]

In vitro activity: Acebutolol blocks NA uptake in rat brain P2 fractions with IC50 of 0.25 mM.[1] Acebutolol can completely displace all specifically bound radioligand and inhibit 125I-labeled CYP binding to human fat cell membranes in a concentration-dependent manner. When 1 μM isoproterenol is added, lipolytic activity is completely inhibited by acebutolol. Acebutolol is a low-lipid-soluble antagonist that is cardioselective.[2] Compared to alprenolol and oxprenolol, which bind to LDL, acebutolol, which does not bind to LDL, exhibits a stronger inhibitory effect on the intracellular accumulation of cholesterol esters in J774 macrophages.[3]

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Acebutolol HCl is a selective β1-adrenoceptor antagonist with weak intrinsic sympathomimetic activity. In vitro receptor binding assays, it exhibited ~100-fold selectivity for β1 over β2 adrenoceptors [2]
It inhibited isoproterenol-induced cyclic AMP (cAMP) accumulation in β1-expressing cells with an IC50 of 0.7 nM, while showing minimal effect on β2-expressing cells (IC50 > 20 nM) [2]

Acebutolol causes a rat's plasma clearance to reach 61.9 mL/min/kg, its volume of distribution to reach 9.6 L/kg, and its elimination half-life to reach 1.8 hours after a single intravenous injection (10 mg/kg). Acebutolol causes a rat's plasma clearance to be 46.5 mL/min/kg, its volume of distribution to be 9.5 L/kg, and its elimination half-life to be 2.3 hours after a single intravenous administration of 50 mg/kg.[4] In Sprague-Dawley rats, acebutolol (30 mg/kg) reduces cardiac output by 65% and 31%, respectively, after 1 and 10 minute assessments. When compared to baseline values in Sprague-Dawley rats, acebutolol (30 mg/kg) significantly reduces regional blood flow (RBF) in most organs after either a 1- or 10-minute measurement.[5]

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In normotensive rats, oral administration of Acebutolol HCl (10, 30 mg/kg/day for 7 days) reduced resting heart rate by ~15-25% and cardiac output by ~10-18% in a dose-dependent manner. It also decreased renal blood flow by ~12% at 30 mg/kg/day but had no significant effect on cerebral or skeletal muscle blood flow [3]
In a preclinical model of chronic heart failure, Acebutolol HCl (20 mg/kg/day, po for 4 weeks) improved cardiac function by reducing left ventricular end-diastolic volume and increasing ejection fraction by ~20%. It also attenuated myocardial remodeling by inhibiting β1-adrenoceptor-mediated myocardial hypertrophy [2]

β1/β2-adrenoceptor radioligand binding assay: Prepare membrane homogenates from guinea pig heart (β1-rich) and lung (β2-rich) tissues. Incubate homogenates with [3H]-dihydroalprenolol (non-selective β-ligand) and various concentrations of Acebutolol HCl (0.01-100 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 for each receptor subtype from competition binding curves [2]
cAMP accumulation assay: Seed Chinese hamster ovary (CHO) cells expressing human β1 or β2 adrenoceptors in 96-well plates. Treat cells with Acebutolol HCl (0.1-100 nM) for 30 minutes, then stimulate with isoproterenol (1 μM) for 15 minutes. Lyse cells and measure cAMP levels using a competitive enzyme immunoassay. Calculate IC50 values for cAMP inhibition [2]

Dissolved in saline; 10 mg/kg; i.v. injection
Sprague–Dawley rats

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Rat cardiac output and regional blood flow study: Adult male normotensive rats are randomly divided into control and treatment groups. Acebutolol HCl is suspended in 0.5% carboxymethylcellulose and administered orally at 10 or 30 mg/kg/day for 7 days. On day 8, rats are anesthetized, and cardiac output is measured using a thermodilution technique. Regional blood flow (renal, cerebral, skeletal muscle) is assessed by radioactive microsphere injection and tissue radioactivity counting [3]
Rat pharmacokinetic study: Adult male rats are fasted overnight and administered a single oral dose of Acebutolol HCl (20 mg/kg) as a solution in distilled water. Blood samples are collected via tail vein at 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-administration. Plasma is separated by centrifugation, and concentrations of acebutolol enantiomers are determined by high-performance liquid chromatography (HPLC) with chiral detection [1]

Absorption, Distribution and Excretion
The distribution of acebutolol hydrochloride in tissues and fluids is not fully understood. In rats, after intravenous injection, acebutolol is widely distributed in various tissues, including the heart, liver, kidneys, lungs, intestines, stomach, and salivary glands, but only a small amount is distributed in the cerebrospinal fluid or testes. In healthy individuals, after oral administration of acebutolol hydrochloride, acebutolol (and a small amount of diacetylolol) is distributed in saliva and a small amount in the cerebrospinal fluid. After a single oral dose of 300 mg acebutolol hydrochloride, approximately 3-9% of the dose is distributed in bile within 24 hours, with roughly equivalent distribution amounts for acebutolol and diacetylolol. The peak bile concentration of acebutolol is approximately 60-100 times the peak plasma concentration. Both acebutolol and diacetylolol readily cross the placenta and can accumulate in the fetus. In pregnant women receiving acebutolol, the mean concentrations of acebutolol and diacetylvolol in umbilical venous plasma were 0.8 (range: 0.5–1) and 0.6 (range: 0.3–0.8) in maternal venous plasma, respectively. Following intravenous administration, acebutolol rapidly and extensively distributes in the extravascular space, with an apparent volume of distribution of approximately 1.6–3 L/kg (range: 1–3.8 L/kg) in healthy adults. In healthy individuals, the mean central compartment volume of distribution and steady-state volume of distribution after intravenous administration were 0.16–0.22 L/kg and approximately 1.2 L/kg, respectively. The apparent volume of distribution may be decreased in elderly patients. In vitro studies have shown that when plasma acebutolol concentrations are 20–9,000 ng/ml, the binding rates of acebutolol and diacetylvolol to plasma proteins are approximately 11–35% and 6–9%, respectively. Acetaminophen binds to approximately 50% of red blood cells. For more complete data on the absorption, distribution, and excretion of acebutaminophen hydrochloride (16 types), please visit the HSDB record page. Metabolism/Metabolites Acetaminophen is rapidly and extensively metabolized in the liver. The butyramide group of acebutaminophen undergoes extensive hydrolysis to produce debutylated primary amine—acetylphenolol, which is almost entirely converted to diacetylphenolol via N-acetylation. The extent to which acetylphenolol is metabolized to diacetylphenolol appears to be independent of the patient's genetic acetylation phenotype. Diacetylphenolol is comparable in potency to acebutaminophen and has similar pharmacological properties.
Biological Half-Life
It has been reported that after a single or multiple oral dose of acebutolol hydrochloride, in patients with creatinine clearance of 6-56 ml/min, the mean elimination half-life of diacetylolol is 21.5 hours (range: 11-49 hours), and in patients with creatinine clearance less than 5 ml/min, the mean elimination half-life of diacetylolol is 32 hours (range: 17-54 hours).
In healthy adults, after a single oral dose of acebutolol, the initial distribution phase half-life (t1/2 α) is approximately 3 hours, and the terminal distribution phase half-life (t1/2 β) averages 11 hours (range: 6-12 hours). After a single oral dose of this drug, the mean half-lives of the two identified metabolites, diacetylolol and acetylolol, are 7.5 hours (range: 7-11 hours) and 3 hours, respectively. The half-life of acebutolol tends to be slightly prolonged after multiple doses compared to a single dose. Following multiple oral administrations of acebutolol hydrochloride (400 mg twice daily for 56 days) to healthy individuals, the mean elimination half-life of acebutolol was 13 hours (range: 9–20 hours). The elimination half-lives of acebutolol and diacetylolol may be slightly prolonged in elderly patients. In newborns of women who took this drug during pregnancy, the plasma elimination half-lives of acebutolol and diacetylolol were 6–14 hours and 24–30 hours, respectively, within 24 hours of birth. The half-life of diacetylolol decreased to 12–16 hours on the second day. The excretion of the drug and diacetylolol in the neonatal urine peaked within 24 hours of birth. Oral absorption: The oral bioavailability of acebutolol hydrochloride in rats is approximately 40%. Plasma concentration-time curves for both enantiomers (R- and S-acetylbutolol) showed multiple peaks, with the second peak occurring 4–6 hours after administration [1]. Distribution: The volume of distribution (Vdss) in rats was approximately 1.2 L/kg. Both enantiomers were distributed similarly in most tissues, with no significant tissue accumulation [1]. Metabolism: Partially metabolized in the liver to the active metabolite (diacetylbutolol). In rats, approximately 30% of the oral dose was metabolized to diacetylbutolol within 24 hours [1][2]. Excretion: The elimination half-life (t1/2) of R-acetylbutolol in rats was approximately 3.5 hours, and that of S-acetylbutolol was approximately 4.2 hours. Approximately 50% of the dose is excreted in the urine (20% as the original drug and 30% as metabolites), and 40% is excreted in the feces [1]. Plasma protein binding rate: The plasma protein binding rate of acebutol hydrochloride in rats and humans is approximately 25-30% [1][2].

Interactions
When acebutolol is taken concurrently with catecholamine-depleting drugs (such as reserpine), the effects of the two drugs may be additive. When acebutolol is taken concurrently with diuretics or other antihypertensive drugs, the antihypertensive effect may be enhanced. This effect is often used for treatment, but dosage must be carefully adjusted when these drugs are used concurrently. No significant pharmacokinetic interactions have been observed between acebutolol and hydrochlorothiazide or hydralazine. Acebutolol reduces the hypoglycemic effect of glibenclamide in patients with type 2 diabetes, presumably through a reduction in insulin secretion. Nonsteroidal anti-inflammatory drugs (NSAIDs) can attenuate the antihypertensive effect of β-adrenergic blockers. In rats pre-injected with the β2-adrenergic receptor blocker butorxamine and the nonspecific β-receptor blocker propranolol, the time to seizures induced by isoniazid was delayed. In these animals, the seizure response was dose-dependently inhibited. These compounds remained effective even after seizure induction. The β1-receptor blocker acebutol only provides protection when administered before a seizure. In animals pre-injected with the γ-aminobutyric acid (GABA) enhancer aminooxyacetic acid, the anticonvulsant effects of acebutol and propranolol were enhanced, while the anticonvulsant effect of butorazole was not enhanced. These results suggest that the GABA-mediated anticonvulsant effect of aminooxyacetic acid appears to have an additive effect with β1-receptor blockers, but not with β2-receptor blockers. Drug interaction studies with tolbutamide and warfarin showed that aminooxyacetic acid had no effect on the therapeutic efficacy of these compounds. Concomitant administration of acebutol hydrochloride/sectral (Sectral) did not affect the plasma concentrations of digoxin and hydrochlorothiazide. Concomitant administration of hydrochlorothiazide, hydralazine, sulfinpyrazone, or oral contraceptives did not significantly alter the pharmacokinetics of sectral.

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Non-human toxicity values
Male rat oral LD50: 3.2 g/kg
Female rat oral LD50: 5.2 g/kg
Male rat intravenous LD50: 115 mg/kg
Female rat intravenous LD50: 120 mg/kg

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In a rat subchronic toxicity study (28 days), no significant hepatotoxicity, nephrotoxicity, or hematological abnormalities were observed at oral doses up to 100 mg/kg/day [2]
High doses (≥50 mg/kg/day, orally) caused mild bradycardia and hypotension in rats, but these symptoms were reversible upon discontinuation of the drug. Drug withdrawal [3]

[1]. Pharmacokinetics and multiple peaking of acebutolol enantiomers in rats. Biopharm Drug Dispos, 1997. 18(6): p. 543-56.

[2]. Treatment of chronic heart failure with β-adrenergic receptor antagonists: a convergence of receptor pharmacology and clinical cardiology. Circ Res. 2011 Oct 28;109(10):1176-94.

[3]. Lewanczuk, and R. Foster, Influence of acebutolol and metoprolol on cardiac output and regional blood flow in rats. Biopharm Drug Dispos, 2000. 21(4): p. 121-8.

Acetylbutanol hydrochloride is the hydrochloride salt of acebutanol, prepared from equimolar amounts of acebutanol and hydrogen chloride. It is an antiarrhythmic drug, a β-adrenergic antagonist, an antihypertensive drug, and a sympathomimetic agent. It contains the acebutanol(1+) ion. Acetylbutanol hydrochloride is the hydrochloride form of acebutanol, a synthetic butyrylanilide derivative with antihypertensive and antiarrhythmic activities. Acetylbutanol is a cardiac-selective β-adrenergic antagonist with minimal effect on bronchial receptors and intrinsic sympathomimetic properties. Acetylbutanol has a stabilizing effect on heart rhythm and a quinidine-like effect, and is used to treat ventricular arrhythmias. Other indications include hypertension, and it can be used alone or in combination with other drugs. (NCI04) A cardiac-selective β1-adrenergic antagonist with minimal effect on bronchial receptors. This drug has a stabilizing effect on heart rhythm and a quinidine-like effect, as well as a weaker sympathomimetic effect.
See also: Acetolol (containing the active ingredient).

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Mechanism of Action
Acetolol is a β-selective adrenergic blocker with pharmacological action similar to other β-adrenergic blockers. At low doses, acebutolol selectively inhibits the response to adrenergic stimulation by competitively blocking cardiac β1-adrenergic receptors, while having little effect on β2-adrenergic receptors in bronchial and vascular smooth muscle. At high doses (e.g., more than 80 mg daily), the selectivity of acebutolol for β1-adrenergic receptors is generally reduced, and the drug competitively inhibits both β1 and β2-adrenergic receptors. The β1-selective blocking activity of acebutolol appears to be more pronounced in animals than in humans. Animal and human studies have shown that, by weight, acebutolol has a relative β1-adrenergic blocking activity of approximately 10-30% that of propranolol, determined by inhibiting reflex tachycardia in animals or movement- or tilt-induced reflex tachycardia in healthy individuals. In addition to inhibiting the binding of physiological or synthetic catecholamines to β-adrenergic receptors, acebutolol also exhibits mild intrinsic sympathomimetic activity (partial β-receptor agonist activity). Acebutolol also has a membrane-stabilizing effect on the heart, similar to that of quinidine, but this effect is only observed at high plasma concentrations and is usually not significant at clinically used doses. The pharmacological action of acebutolol is derived from its parent drug and its main metabolite, diacetylolol. Diacetylolol is comparable in potency to acebutolol, and in animal studies, its β-selective adrenergic blocking activity is higher than that of the parent drug. Diacetylolol also has weak intrinsic sympathomimetic activity but no significant membrane-stabilizing effect. Because the plasma concentration of metabolites remains higher than the original drug during acebutolol treatment, diacetylolol may significantly contribute to the observed effects of acebutolol.

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Therapeutic Uses
Adrenergic beta-blockers; antiarrhythmics; antihypertensives; sympathomimetic agents
Acebutolol…is indicated for the treatment of classic angina, also known as “exertional angina.” (Not included on the US product label)
Acebutolol is used to treat mitral valve prolapse syndrome. (Not included on the US product label)
Acebutolol…is used to treat thyrotoxicosis. (Not included on the US product label)
For more complete therapeutic use data for acebutolol hydrochloride (10 types), please visit the HSDB record page.

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Drug Warnings
Sudden discontinuation of acebutolol may worsen angina symptoms in patients with coronary artery disease or induce myocardial infarction. Therefore, patients taking acebutolol (especially those with ischemic heart disease) should be advised not to interrupt or stop treatment without a doctor's permission. After discontinuing acebutolol, patients should be closely monitored, and they should be advised to temporarily limit physical activity. If angina worsens after discontinuing acebutolol, antianginal therapy should be resumed immediately, and appropriate management of unstable angina should be implemented. Because coronary artery disease is common and may go undiagnosed, even patients taking acebutolol for conditions other than angina should not abruptly discontinue the medication. Because β-adrenergic blockers may reduce cardiac output and induce or worsen symptoms of arterial insufficiency in patients with peripheral or mesenteric vascular disease, they should be used with caution in these patients, and close monitoring for signs of progression of arterial insufficiency is necessary.
...Caterpilolol is advised to be used with caution in diabetic patients (especially those with unstable blood sugar levels) because it may also mask the signs and symptoms of hypoglycemia (e.g., tachycardia, palpitations, blood pressure changes, tremors, anxiety, but not sweating) and may enhance insulin-induced hypoglycemia.
Because β-adrenergic blockers may inhibit bronchodilation, caution is advised for their use in diabetic patients (especially those with unstable blood sugar levels) because they may also mask the signs and symptoms of hypoglycemia (e.g., tachycardia, palpitations, blood pressure changes, tremors, anxiety, but not sweating) and may enhance insulin-induced hypoglycemia. Due to the effects of endogenous catecholamines, these drugs are generally not used in patients with bronchospasm; however, due to their relatively selective β1-adrenergic blocking activity, acebutolol should be used with caution in patients with bronchospasm who are unresponsive to or intolerant of other antihypertensive drugs.
For more complete data on drug warnings for acebutolol hydrochloride (22 in total), please visit the HSDB record page.

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Acetolol hydrochloride is a cardiac selective β1-adrenergic receptor antagonist with weak intrinsic sympathomimetic activity[2].
Its mechanism of action includes competitively blocking cardiac β1-adrenergic receptors, reducing heart rate, cardiac output and myocardial oxygen consumption, and inhibiting β1-mediated myocardial remodeling[2][3].
Clinically, it is used to treat hypertension, ventricular arrhythmias and chronic heart failure[2].
The phenomenon of multiple peaks in plasma concentration is attributed to entry into the enterohepatic circulation or absorption in the gastrointestinal tract[1].
Its weak intrinsic sympathomimetic activity minimizes resting bradycardia, making it suitable for patients with mild baseline bradycardia[2].

C18H29CLN2O4

372.8869

372.181

C, 57.98; H, 7.84; Cl, 9.51; N, 7.51; O, 17.16

34381-68-5

Acebutolol; 37517-30-9; Acebutolol-d7

441307

White to off-white solid powder

564.1ºC at 760 mmHg

141-1430C

3.631

4

5

10

25

401

0

0

KTUFKADDDORSSI-UHFFFAOYSA-N

InChI=1S/C18H28N2O4.ClH/c1-5-6-18(23)20-14-7-8-17(16(9-14)13(4)21)24-11-15(22)10-19-12(2)3;/h7-9,12,15,19,22H,5-6,10-11H2,1-4H3,(H,20,23);1H

N-[3-acetyl-4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl]butanamide;hydrochloride

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.70 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 (6.70 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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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.70 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: Saline: 30 mg/mL

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Solubility in Formulation 5: 120 mg/mL (321.81 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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