β1 adrenoceptor

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]

Absorption, Distribution and Excretion
Distribution of acebutolol hydrochloride into body tissue and fluids has not been fully characterized. Following IV administration in rats, acebutolol is distributed extensively into many tissues, including heart, liver, kidneys, lungs, intestines, stomach, and salivary glands, but only minimally into CSF or testes. Following oral administration of acebutolol hydrochloride in healthy individuals, acebutolol and, to a lesser extent, diacetolol, are distributed into saliva and minimally into CSF. Following oral administration of a single 300-mg dose of acebutolol hydrochloride, about 3-9% of the dose is distributed into bile within 24 hours, in approximately equivalent amounts as acebutolol and diacetolol. Peak biliary concentrations of acebutolol are approximately 60-100 times greater than peak plasma concentrations.
Acebutolol and diacetolol readily cross the placenta and can accumulate in the fetus. In pregnant women receiving acebutolol, the mean acebutolol and diacetolol ratios of umbilical venous to maternal venous plasma concentrations were 0.8 (range: 0.5-1) and 0.6 (range: 0.3-0.8), respectively.
Following IV administration, acebutolol is rapidly and widely distributed into the extravascular space and the apparent volume of distribution of the drug in healthy adults is approximately 1.6-3 l/kg (range: 1-3.8 l/kg). In healthy individuals, the volume of distribution in the central compartment and at steady state averages 0.16-0.22 and approximately 1.2 l/kg, respectively, following IV administration. The apparent volume distribution may be decreased in geriatric patients.
In vitro, acebutolol and diacetolol are approximately 11-35 and 6-9% bound, respectively, to plasma proteins at plasma acebutolol concentrations of 20-9,000 ng/ml. Acebutolol is approximately 50% bound to erythrocytes.
For more Absorption, Distribution and Excretion (Complete) data for ACEBUTOLOL HYDROCHLORIDE (16 total), please visit the HSDB record page.

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Metabolism / Metabolites
Acebutolol is rapidly and extensively metabolized in the liver. Acebutolol undergoes extensive hydrolysis of the butyramide group to form the desbutyl primary amine, acetolol, which is almost completely converted via N-acetylation to diacetolol. The extent of metabolism of acebutolol to diacetolol appears to be independent of the genetic acetylator phenotype of the patient. Diacetolol is equipotent to acebutolol and has a similar pharmacologic profile.

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Biological Half-Life
Following single or mutiple oral doses of acebutolol hydrochloride, the elimination half-life of diacetolol reportedly averages 21.5 hours (range: 11-49 hours) or 32 hours (range: 17-54 hours) in patients with creatinine clearances of 6-56 or less than 5 ml/minute, respectively.
Following a single oral dose in healthy adults, the half-life of acebutolol in the initial distrubution phase (t1/2 alpha) is about 3 hours and the half-life in the terminal phase (t1/2 beta) has been reported to average 11 hours (range: 6-12 hours). The half-lives of the two identified metabolites, diacetolol and acetolol, average 7.5 (range: 7-11 hours) and 3 hours, respectively, following a single oral dose of the drug. The half-life of acebutolol tends to be slightly prolonged following multiple rather than single doses. Following multiple-dose oral administration of acebutolol hyrochloride in healthy individuals (400 mg twice daily for 56 days), the elimination half-life of acebutolol average 13 hours (range: 9-20 hours). The elimination half-lives of acebutolol and diacetolol may be slightly iincreased in geriatric patients.
The plasma elimination half-lives of acebutolol and diacetolol in neonates born to women receiving the drug during pregnancy ranged from 6-14 and from 24-30 hours, respectively, in the first 24 hours after birth; the half-life of diacetolol decreased to 12-16 hours during the second day. Neonatal urinary excretion of the drug and diacetolol was maximal during the first 24 hours after birth.

Interactions
When acebutolol and a catecholamine-depleting drug (eg, reserpine) are administered concomitantly, the effects of the drugs may be additive.
When acebutolol is administered with diuretics or other hypotensive agents, the hypotensive effect may be increased. This effect usually is used to therapeutic advantage, but careful adjustment of dosage is necessary when these drugs are used concomitantly. No substantial pharmacokinetic interactions between acebutolol and hydrochlorothiazide or hydralazine have been observed.
Acebutolol has decreased the hypoglycemic action of glyburide in type II diabetic patients, presumably by decreasing insulin secretion. Nonsteroidal anti-inflammatory agents have blunted the hypotensive effects of beta-adrenergic blocking agents.
A delay in the onset of isoniazid induced convulsions was found in rats pretreated with the beta 2-adrenoceptor blocker, butoxamine, and the nonspecific beta-blocker, propranolol. In these animals the convulsive responses were inhibited in a dose dependent manner. These compounds were found to be effective even after the induction of convulsions. The beta-1-blocker, acebutolol was able to protect rats only when injected prior to the challenge. The anticonvulsant effect of acebutolol and propranolol but not that of butoxamine was found to be enhanced in animals pretreated with a gamma-aminobutyric acid elevating agent, aminooxyacetic acid. The findings indicate that the gamma-aminobutyric acid mediated anticonvulsant action of aminooxyacetic acid seems to be additive with that resulting from beta-1 but not beta-2-blockade.
Drug interaction studies with tolbutamide and warfarin indicated no influence on the therapeutic effects of these compounds. Digoxin and hydrochlorothiazide plasma levels were not affected by concomitant Sectral /acebutolol hydrochloride/ administration. The kinetics of sectral were not significantly altered by concomitant administration of hydrochlorothiazide, hydralazine, sulfinpyrazone, or oral contraceptives.

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Non-Human Toxicity Values
LD50 Rat (male) oral 3.2 g/kg
LD50 Rat (female) oral 5.2 g/kg
LD50 Rat (male) iv 115 mg/kg
LD50 Rat (female) iv 120 mg/kg)

[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.

Acebutolol hydrochloride is the hydrochloride salt of acebutolol, prepared using equimolar amounts of acebutolol and hydrogen chloride. It has a role as an anti-arrhythmia drug, a beta-adrenergic antagonist, an antihypertensive agent and a sympathomimetic agent. It contains an acebutolol(1+).
Acebutolol Hydrochloride is the hydrochloride salt form of acebutolol, a synthetic butyranilide derivative with hypotensive and antiarrhythmic activity. Acebutolol acts as a cardioselective beta-adrenergic antagonist with little effect on bronchial receptors and has intrinsic sympathomimetic properties. Having stabilizing and quinidine-like effects on cardiac rhythm, Acebutolol is used in ventricular arrhythmias. Other indications include hypertension, alone or in combinations with other agents. (NCI04)
A cardioselective beta-1 adrenergic antagonist with little effect on the bronchial receptors. The drug has stabilizing and quinidine-like effects on cardiac rhythm, as well as weak inherent sympathomimetic action.
See also: Acebutolol (has active moiety).

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Mechanism of Action
Acebutolol is a beta-selective adrenergic blocking agent and has pharmacologic actions similar to those of other beta-adrenergic blocking agents. At low dosages, acebutolol selectively inhibits response to adrenergic stimuli by competively blocking cardiac beta1-adrenergic receptors, while having little effect on the beta2-adrenergic receptors of bronchial and vascular smooth muscle. At high dosages (eg, greater than 80 mg daily), the selectively of acebutolol for beta-1-adrenergic receptors usually diminishes, and the drug will competively inhibit beta-1- and beta-2-adrenergic receptors. The beta1-selective blocking activity of acebutolol appears to be more pronounced in animals than in humans. In vivo studies in animals and humans indicate that the relative beta-1-adrenergic blocking activity of acebutolol, on a weight basis, is approximately 10-30% that of propranolol, as determined by inhibition of reflex tachycardia in animals or inhibition of exercise or tilt-induced or reflex tachycardia in healthy individuals.
In addition to inhibiting access of physiologic or synthetic catecholamines to beta-adrenergic receptors, acebutolol exhibits mild intrinsic sympathomimetic activity (partial beta-agonist activity). Acebutolol also has a membrane-stabilizing effect on the heart, which is similar to that of quinidine but occurs only at high plasma concentrations and usually is not apparent at dosages used clinically.
The pharmacologic effects of acebutolol results from both the unchanged drug and its major metabolite, diacetolol. Diacetolol is equipotent to acebutolol and, in animals, has greater beta-selective adrenergic blocking activity than the parent drug. Diacetolol also has weak intrinsic sympathomimetic activity but does not have substantial membrane-stabilizing activity. Diacetolol may contribute substantially to the observed effects of acebutolol, since plasma concentrations of the metabolite are consistently higher than those of the parent during acebutolol therapy.

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Therapeutic Uses
Adrenergic beta-Antagonists; Anti-Arrhythmia Agents; Antihypertensive Agents; Sympatholytics
Acebutolol ... /is/ indicated in the treatment of classic angina pectoris, also referred to as "effort-associated angina". /NOT included in US product labeling/
Acebutolol /is/ used in the treatment of mitral value prolapse syndrome. /NOT included in US product labeling/
Acebutolol ... /is/ used for thyrotoxicosis. /NOT included in US product labeling/
For more Therapeutic Uses (Complete) data for ACEBUTOLOL HYDROCHLORIDE (10 total), please visit the HSDB record page.

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Drug Warnings
Abrupt withdrawal of acebutolol may exacerbate angina symptoms or precipitate myocardial infarction in patients with corornary artery disease. Therefore, patients receiving acebutolol (especially those with ischemic heart disease) should be warned not to interrupt or discontinue therapy without consulting their physician. When acebutolol therapy is discontinued, patients should be monitored carefully and advised to temporarily limit their physical activity. If exacerbation of angina occurs after acebutolol therapy is interrupted, antianginal therapy should be reinstituted promptly, and appropriate measures for the management of unstable angina pectoris should be initiated. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue acebutolol therapy abruptly, even in patients receiving the drug for conditions other than angina.
Since beta-adrenergic blocking agents may reduce cardiac output and precipitate or aggravate the symptoms of arterial insufficiency in patients with peripheral or mesenteric vascular disease, acebutolol should be used with caution in these patients, and the patients should be observed for evidence of progression of arterial insufficiency.
... It is recommended that acebutolol be used with caution in patients with diabetes mellitus (especially those with labile diabetes) since the drug also may mask signs and symptoms of hypoglycemia (e.g., tachycardia, palpitation, blood pressure changes, tremor, feelings of anxiety, but not sweating) and may potentiate insulin-induced hypoglycemia.
Since beta-adrenergic blocking agents may inhibit bronchodilation produced by endogenous catecholamines, the drugs generally should not be used in patients with bronchospastic disease; however, because of its relative beta 1-selective adrenergic blocking activity, acebutolol may be used with caution in patients with bronchospastic disease who do not respond to or cannot tolerate other hypotensive agents.
For more Drug Warnings (Complete) data for ACEBUTOLOL HYDROCHLORIDE (22 total), please visit the HSDB record page.

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.)