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Analytical and Bioanalytical Chemistry Jul 2013A comparative study of the electrochemical conversion and the biotransformation performed by the cytochrome P450 (CYP450) obtained by rat liver microsomes has been... (Comparative Study)
Comparative Study
Acebutolol and alprenolol metabolism predictions: comparative study of electrochemical and cytochrome P450-catalyzed reactions using liquid chromatography coupled to high-resolution mass spectrometry.
A comparative study of the electrochemical conversion and the biotransformation performed by the cytochrome P450 (CYP450) obtained by rat liver microsomes has been achieved to elucidate the oxidation mechanism of both acebutolol and alprenolol. For this purpose, a wide range of reactions such as N-dealkylation, O-dealkoxylation, aromatic hydroxylation, benzyl hydroxylation, alkyl hydroxylation, and aromatic hydroxylation have been examined in this study, and their mechanisms have been compared. Most of the results of the electrochemical oxidation have been found to be in accordance with those obtained by incubating acebutolol and alprenolol in the presence of CYP450, i.e., N-dealkylation, benzyl hydroxylation, and O-dealkoxylation reactions catalyzed by liver microsomes were found to be predicted by the electrochemical oxidation. The difficulty for the electrochemical process to mimic both aromatic and alkyl hydroxylation reactions has also been discussed, and the hypothesis for the absence of aromatic hydroxylated and alkyl hydroxylated products, respectively, for alprenolol and acebutolol, under the anodic oxidation has been supported by theoretical calculation. The present study highlights the potential and limitation of coupling of electrochemistry-liquid chromatography-high-resolution mass spectrometry for the study of phase I and phase II reactions of acebutolol and alprenolol.
Topics: Acebutolol; Alprenolol; Animals; Catalysis; Chromatography, Liquid; Cytochrome P-450 Enzyme System; Dealkylation; Electrochemical Techniques; Hydroxylation; Mass Spectrometry; Microsomes, Liver; Models, Theoretical; Oxidation-Reduction; Rats
PubMed: 23700103
DOI: 10.1007/s00216-013-7050-7 -
European Journal of Clinical... Oct 1977Acebutolol, a new cardioselective beta-adrenoceptor blocking agent, has been evaluated for the treatment of hypertension. Thirty eight previously untreated male patients... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Acebutolol, a new cardioselective beta-adrenoceptor blocking agent, has been evaluated for the treatment of hypertension. Thirty eight previously untreated male patients with essential hypertension received placebo treatment during a 4-week run-in period, and then they were randomly (double-bind) allocated either to continued placebo treatment for three 4-week periods or to treatment with acebutolol 400, 600, and 1200 mg daily, respectively, for three 4-week periods. Blood pressure and heart rate were recorded at the end of each 4-week period. Treatment with acebutolol produced statistically significant reductions in blood pressure and heart rate as compared to the placebo regimen.
Topics: Acebutolol; Blood Pressure; Clinical Trials as Topic; Double-Blind Method; Heart Rate; Humans; Hypertension; Male; Middle Aged; Placebos
PubMed: 336378
DOI: 10.1007/BF00645127 -
Circulation Jun 1982The safety and efficacy of acebutolol in suppressing ventricular ectopy was evaluated in 60 males (average 59 years) using 24-hour Holter recordings and a double-blind,... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
The safety and efficacy of acebutolol in suppressing ventricular ectopy was evaluated in 60 males (average 59 years) using 24-hour Holter recordings and a double-blind, randomized, crossover protocol. Acebutolol, 200 mg and 400 mg thrice daily, was compared with placebo. Only patients who had a mean of at least 30 ventricular premature complexes (VPCs) per hour on three 24-hour control Holter recordings were included. Analysis of Holter recordings revealed greater than 70% reduction in VPCs/hour from control levels during acebutolol therapy in over 50% of the 60 patients; dose-related reduction in the mean number of single and paired VPCs and ventricular tachycardia episodes (p less than 0.05) by acebutolol; and significant, asymptomatic reduction in resting heart rate and blood pressure. All side effects were transient. Acebutolol was discontinued because of side effects in one patient only.
Topics: Acebutolol; Adult; Aged; Arrhythmias, Cardiac; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Heart Ventricles; Humans; Male; Middle Aged; Random Allocation
PubMed: 7042111
DOI: 10.1161/01.cir.65.6.1129 -
Annales Pharmaceutiques Francaises Sep 2021The aim of this study was to predict the plasma concentrations of acebutolol tablets with different dissolution profiles using computer modelling and evaluating whether...
PURPOSE
The aim of this study was to predict the plasma concentrations of acebutolol tablets with different dissolution profiles using computer modelling and evaluating whether they are bioequivalent using simulated population studies.
METHODS
The dissolution behaviour of acebutolol was studied in the USP Apparatus-II using different dissolution media for pH 1.2, 4.5, and 6.8 at 37±0.5°C. The obtained dissolution data, as well as plasma concentration-time data of the reference product from the literature were used as inputs to build pharmacokinetic model of acebutolol within GastroPlus™ software (version 9.7, Simulations Plus Inc., Lancaster, CA, USA) to simulate the in vivo profiles of the drug.
RESULTS
The dissolution profiles of the reference product Sectral® 400mg tablets and a locally produced generic product were>85% in 15min in three dissolution media. Simulation results demonstrated that the brand and generic products would show the same in vivo performance. Population simulation results of the ln-transformed 90% confidence interval for the ratio of C, AUC and AUC values for the two products were within the 80-125% interval, showing to be bioequivalent.
CONCLUSION
Based on the in vitro results combined with in silico simulations using GastroPlus™, a biowaiver for immediate release acebutolol tablets is justified. Furthermore, computer modelling has shown to be a very intersting tool to prove the bioequivalence for these products.
Topics: Acebutolol; Computer Simulation; Solubility; Tablets; Therapeutic Equivalency
PubMed: 33675740
DOI: 10.1016/j.pharma.2021.02.004 -
British Heart Journal Jan 1978
Clinical Trial
Topics: Acebutolol; Clinical Trials as Topic; Coronary Artery Bypass; Heart Transplantation; Hemodynamics; Humans; Methods; Myocardial Contraction; Transplantation, Homologous
PubMed: 341929
DOI: 10.1136/hrt.40.1.29 -
American Heart Journal May 1985Studies in various animal models have shown acebutolol to be a relatively cardioselective beta-adrenoceptor-blocking agent possessing both partial agonist and...
Studies in various animal models have shown acebutolol to be a relatively cardioselective beta-adrenoceptor-blocking agent possessing both partial agonist and membrane-stabilizing activities. The latter property may not be significant at clinically used doses. Acebutolol has both antihypertensive and antiarrhythmic effects. As with beta blockers in general, the antihypertensive mechanism of acebutolol is not known. The antiarrhythmic activity of acebutolol may be related to beta blockade. Acebutolol is relatively hydrophilic and does not readily cross the blood-brain barrier, a fact that may be clinically significant in reducing the frequency and severity of central nervous system adverse effects. The pharmacologic profile of diacetolol, acebutolol's major metabolite, is similar to that of the parent compound in beta-blocking potency, cardioselectivity, and partial agonist activity. Diacetolol, however, does not possess membrane-stabilizing activity.
Topics: Acebutolol; Adrenergic beta-Antagonists; Animals; Arrhythmias, Cardiac; Blood-Brain Barrier; Cats; Cell Membrane; Dogs; Guinea Pigs; Hypertension; Lipid Metabolism; Propranolol; Solubility; Sotalol
PubMed: 2859774
DOI: 10.1016/0002-8703(85)90695-7 -
Clinical Pharmacology and Therapeutics Apr 1976Using a balance, randomized, crossover design, single intravenous (1 mg/kg) or oral (3 X 100 mg) doses of acebutolol were administered at weekly intervals to 6 healthy... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Using a balance, randomized, crossover design, single intravenous (1 mg/kg) or oral (3 X 100 mg) doses of acebutolol were administered at weekly intervals to 6 healthy volunteers. For each subject venous blood samples and timed urine collections were obtained after each treatment. Plasma and urinary acebutolol levels were measured by a spectrophotometric method that measures acebutolol and its N-acetyl metabolite (which has equivalent cardiac activity). Using a computer program, various pharmacokinetic parameters were estimated from the date of each subject. From the intravenous data (obtained up to 6 hr after dosing), the following mean (+/-SD) values were found: distribution half-life (T 1/2D), 0.60 (+/-0.43) hr, plasma elimination half-life (T 1/2El), 3.2 (+/-1.1) hr, apparent volume of distribution (VD), 224 (+/-69) L, and apparent VD/kg, 3.0 (+/-0.8) L/kg. Using the oral data (obtained up to 10 hr after dosing), the value for T 1/2El was 3.2 (+/-0.9) hr. The mean cumulative urinary recovery (expressed as % dose) after the intravenous route was about 60%, while that after the oral route was of the order of 35%, suggesting that about half of the oral dose reached the systemic circulation. The mean creatinine clearance of the 6 subjects was 103 (+/-7) ml/min, while the value (obtained between 2 and 4 hr after intravenous dosing) for renal clearance of acebutolol as measured was 298 (+/-68) ml/min and the corresponding plasma clearance was 818 (+/-64) ml/min. These results support the occurrence of substantial nonrenal elimination and renal tubular secretion.
Topics: Acebutolol; Administration, Oral; Adult; Computers; Creatinine; Half-Life; Humans; Injections, Intravenous; Kinetics; Male
PubMed: 1269192
DOI: 10.1002/cpt1976194416 -
American Heart Journal May 1985Two double-blind multicenter studies compared acebutolol with placebo (acebutolol, N = 121; placebo, N = 116) and with propranolol (acebutolol, N = 186; propranolol, N =... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
Two double-blind multicenter studies compared acebutolol with placebo (acebutolol, N = 121; placebo, N = 116) and with propranolol (acebutolol, N = 186; propranolol, N = 190) in essential hypertension. Acebutolol significantly reduced mean sitting diastolic blood pressure from 99.2 +/- 0.3 mm Hg at baseline to 89.1 +/- 0.9 mm Hg at the end of dose titration (p = 0.001). Significantly more acebutolol patients (65%) achieved therapeutic goal than did placebo patients (28%, p less than 0.01). The reduction in heart rate in acebutolol-treated patients (9.2 bpm) was greater than in placebo-treated patients (1.2 bpm, p = 0.001). The incidence of side effects and the number of patients discontinued because of side effects did not significantly differ between acebutolol and placebo. Acebutolol and propranolol produced comparable reductions in diastolic, systolic, and mean arterial blood pressures (p less than 0.001). At equipotent doses the 13% decrease in heart rate in patients receiving acebutolol was significantly less than the 17% decrease in propranolol patients (p = 0.02). The number of patients experiencing central nervous system (CNS) side effects while receiving acebutolol (N = 50) was significantly less than with propranolol (N = 75, p = 0.001), and significantly fewer acebutolol patients (N = 11) were discontinued because of side effects compared with propranolol patients (N = 29, p less than 0.01). Laboratory, ECG, or chest X-ray results did not differ for acebutolol, placebo, or propranolol. Acebutolol appears to be safe and effective in the management of mild to moderately severe essential hypertension and is better tolerated than propranolol in terms of CNS side effects, with a significantly lesser effect on heart rate.
Topics: Acebutolol; Adrenergic beta-Antagonists; Adult; Aged; Body Weight; Clinical Trials as Topic; Double-Blind Method; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Placebos; Propranolol; Random Allocation
PubMed: 2859780
DOI: 10.1016/0002-8703(85)90702-1 -
Circulation May 1977The antiarrhythmic action of the beta-blocking drug, acebutolol, was evaluated in patients with frequent premature ventricular contractions (PVCs). In the 12 hours...
The antiarrhythmic action of the beta-blocking drug, acebutolol, was evaluated in patients with frequent premature ventricular contractions (PVCs). In the 12 hours following administration of a single 300 mg oral dose, 8 of 10 patients showed a greater than 50% reduction in PVC frequency, and statistical analysis indicated that PVC reduction persisted for 10 hours after the single dose. Analysis of plasma concentrations of acebutolol and an acetyl metabolite indicated that after single oral doses of plasma concentrations of the metabolite exceed those of unchanged acebutolol. When patients were studied during periods of 300 mg doses every 8 hours, eight of 11 showed a 70% reduction in PVC frequency, and analysis showed that the therapeutic effect was present throughout the 24-hour monitoring period. Acebutolol slowed the heart rate and prolonged the PR interval without affecting the QT interval. Significant clinical or laboratory toxicity was not encountered. In the small group studied, acebutolol was found to be safe and effective for short-term administration to patients with frequent PVCs and possessed a relatively long duration of antiarrhythmic action.
Topics: Acebutolol; Aged; Cardiac Complexes, Premature; Drug Evaluation; Electrocardiography; Female; Heart Conduction System; Heart Rate; Humans; Male; Methods; Middle Aged; Myocardial Infarction
PubMed: 66105
DOI: 10.1161/01.cir.55.5.785 -
American Heart Journal May 1985Acebutolol was compared to placebo, propranolol, and quinidine for the suppression of chronic ventricular arrhythmia in three double-blind, randomized crossover studies.... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
Acebutolol was compared to placebo, propranolol, and quinidine for the suppression of chronic ventricular arrhythmia in three double-blind, randomized crossover studies. Patients averaged greater than or equal to 10 to 30 premature ventricular contractions (PVCs) per hour in the baseline periods. Compared to baseline in all three studies, acebutolol significantly (p less than 0.002 to p less than 0.001) reduced mean total PVCs and complex PVCs. In all measurements, acebutolol was superior to placebo (p less than 0.02 to p less than 0.001) and comparable to propranolol and quinidine. During acebutolol treatment, 39% of the patients had reductions of greater than or equal to 75% in mean hourly PVC frequency compared to 23% during placebo treatment (p = 0.02). Similar numbers of patients had greater than or equal to 75% reductions during acebutolol treatment in comparison with propranolol and quinidine. Acebutolol was better tolerated than quinidine and produced an antiarrhythmic effect equivalent to that of propranolol, with a significantly (p less than 0.01) lesser decrease in resting heart rate. The antiarrhythmic activity of acebutolol, its ancillary pharmacologic properties, and its tolerance by a diverse group of patients make acebutolol a significant tool for the clinician in the management of chronic arrhythmia.
Topics: Acebutolol; Adult; Aged; Arrhythmias, Cardiac; Double-Blind Method; Female; Humans; Male; Middle Aged; Placebos; Propranolol; Quinidine; Random Allocation
PubMed: 3993535
DOI: 10.1016/0002-8703(85)90709-4