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Evaluation of Drug-Drug Interactions via Inhibition of Hydrolases by Orlistat, an Anti-Obesity Drug.Drug Metabolism and Disposition: the... Aug 2023Drug-drug interactions (DDI) have a significant impact on drug efficacy and safety. It has been reported that orlistat, an anti-obesity drug, inhibits the hydrolysis of...
Drug-drug interactions (DDI) have a significant impact on drug efficacy and safety. It has been reported that orlistat, an anti-obesity drug, inhibits the hydrolysis of -nitrophenol acetate, a common substrate of the major drug-metabolizing hydrolases, carboxylesterase (CES) 1, CES2, and arylacetamide deacetylase (AADAC), in vitro. The aim of this study was to examine whether orlistat affects the pharmacokinetics of drug(s) metabolized by hydrolases in vivo after evaluating its inhibitory potencies against CES1, CES2, and AADAC in vitro. Orlistat potently inhibited the hydrolysis of acebutolol, a specific substrate of CES2, in a non-competitive manner (inhibition constant, = 2.95 ± 0.16 nM), whereas it slightly inhibited the hydrolysis of temocapril and eslicarbazepine acetate, specific substrates of CES1 and AADAC, respectively (IC >100 nM). The in vivo DDI potential was elucidated using mice, in which orlistat showed strong inhibition against acebutolol hydrolase activities in the liver and intestinal microsomes, similar to humans. The area under the curve (AUC) of acebutolol was increased by 43%, whereas the AUC of acetolol, a hydrolyzed metabolite of acebutolol, was decreased by 47% by co-administration of orlistat. The ratio of the value to the maximum unbound plasma concentration of orlistat (<0.012) is lower than the risk criteria for DDI in the liver defined by the US Food and Drug Administration guideline (>0.02), whereas the ratio of the value to the estimated intestinal luminal concentration (3.3 × 10) is considerably higher than the risk criteria in the intestine (>10). Therefore, this suggests that orlistat causes DDI by inhibiting hydrolases in the intestine. SIGNIFICANCE STATEMENT: This study demonstrated that orlistat, an anti-obesity drug, causes drug-drug interactions in vivo by potently inhibiting carboxylesterase 2 in the intestine. This is the first evidence that inhibition of hydrolases causes drug-drug interactions.
Topics: Humans; Mice; Animals; Hydrolases; Orlistat; Carboxylic Ester Hydrolases; Anti-Obesity Agents; Acebutolol; Carboxylesterase; Pharmaceutical Preparations; Hydrolysis; Drug Interactions
PubMed: 37137721
DOI: 10.1124/dmd.123.001266 -
Die Pharmazie Sep 2022H/D exchange reactions can be observed by NMR spectroscopy of acebutolol (ACE). The results obtained showed deuterium incorporation at α-posi t ion of the carbonyl...
H/D exchange reactions can be observed by NMR spectroscopy of acebutolol (ACE). The results obtained showed deuterium incorporation at α-posi t ion of the carbonyl group of acebutolol, when using deuterium oxide or deuterated methanol as deuterium source and solvent. The spontaneous deuteration is proceeded by the following pathway CH₃→CH₂D→CHD→CD₃, through a keto-enol tautomerization reaction. Furthermore, LC-MS / QTOF analyses have confirmed the proposed H/D exchange. In order to reduce the time of total deuteration observed at the acetyl group alkaline catalysts were employed.
Topics: Acebutolol; Deuterium; Deuterium Oxide; Hydrogen; Methanol; Solvents
PubMed: 36199187
DOI: 10.1691/ph.2022.2419 -
Molecules (Basel, Switzerland) Oct 2019A wooden stick coated with a novel graphene-based nanocomposite (Graphene oxide/polyethylene glycol (GO/PEG)) is introduced and investigated for its efficacy in solid...
A wooden stick coated with a novel graphene-based nanocomposite (Graphene oxide/polyethylene glycol (GO/PEG)) is introduced and investigated for its efficacy in solid phase microextraction techniques. The GO/PEG-stick was prepared and subsequently applied for the extraction of β-blockers, acebutolol, and metoprolol in human oral fluid samples, which were subsequently detected by liquid chromatography tandem mass spectrometry (LC-MS/MS). Experimental parameters affecting the extraction protocol including sample pH, extraction time, desorption time, appropriate desorption solvent, and salt addition were optimized. Method validation for the detection from oral fluid samples was performed following FDA (Food and Drug Administration) guidelines on bioanalytical method validation. Calibration curves ranging from 5.0 to 2000 nmol L for acebutolol and 25.0 to 2000 nmol L for metoprolol were used. The values for the coefficient of determination (R) were found to be 0.998 and 0.996 ( = 3) for acebutolol and metoprolol, respectively. The recovery of analytes during extraction was 80.0% for acebutolol and 62.0% for metoprolol, respectively. The limit of detections (LODs) were 1.25, 8.00 nmol L for acebutolol and metoprolol and the lower limit of quantifications (LLOQ) were 5.00 nmol L for acebutolol and 25.0 nmol L for metoprolol. Validation experiments conducted with quality control (QC) samples demonstrated method accuracy between 80.0% to 97.0% for acebutolol and from 95.0% to 109.0% for metoprolol. The inter-day precision for QC samples ranged from 3.6% to 12.9% for acebutolol and 9.5% to 11.3% for metoprolol. Additionally, the GO/PEG-stick was demonstrated to be reusable, with the same stick observed to be viable for more than 10 extractions from oral fluid samples.
Topics: Acebutolol; Adrenergic beta-Antagonists; Body Fluids; Chromatography, Liquid; Graphite; Humans; Limit of Detection; Metoprolol; Mouth; Nanocomposites; Polyethylene Glycols; Solid Phase Microextraction; Tandem Mass Spectrometry
PubMed: 31614604
DOI: 10.3390/molecules24203664 -
Heliyon Oct 2023A straightforward approach for creating fast and novel potentiometric sensors that are modified with multi-walled nanotubes (MWCNTs) was described. The impact of the...
Fast and novel multiwalled carbon nanotubes decorated with metal oxide nanoparticles for potentiometric detection of a prohibited medication in sports acebutolol hydrochloride.
A straightforward approach for creating fast and novel potentiometric sensors that are modified with multi-walled nanotubes (MWCNTs) was described. The impact of the selective sensor's material was studied. The suggested sensors were successfully fabricated for instant and fast detection of the prohibited β-adrenoreceptor blocking agent acebutolol hydrochloride (AC) in commercial products. Acebutolol-phosphomolybdate (AC-PM) carbon paste sensor was formed by mixing AC and phosphomolybdic acid and graphite powder in the presence of -nitrophenyl octyl ether (-NPOE) as a plasticizing agent. The functionalized AC-PM-MWCNTs and AC-PM-MWCNTs-AlO nanocomposite sensors were prepared and all parameters affecting the sensors' potential responses have been investigated as well as the green synthesis of AlONPs has been characterized using various microscopic and spectroscopic techniques. AC-PM-MWCNTs and AC-PM-MWCNTs-AlO nanocomposite sensors demonstrated linearity of 1.0 × 10-1.0 × 10 and 1.0 × 10-1.0 × 10 mol L, respectively with regression equations -53.571x + 423.24 (r = 0.999) and -57.107x + 518.54 (r = 0.999). It also revealed excellent selectivity and sensitivity for the determination and quantification of AC. The developed potentiometric system was suitable for the determination of AC in bulk powder and commercial products.
PubMed: 37876475
DOI: 10.1016/j.heliyon.2023.e20997 -
Chirality Jun 2015A new chemoenzymatic route is reported to synthesize acebutolol, a selective β1 adrenergic receptor blocking agent in enantiopure (R and S) forms. The enzymatic kinetic...
A new chemoenzymatic route is reported to synthesize acebutolol, a selective β1 adrenergic receptor blocking agent in enantiopure (R and S) forms. The enzymatic kinetic resolution strategy was used to synthesize enantiopure intermediates (R)- and (S)-N-(3-acetyl-4-(3-chloro-2-hydroxypropoxy)phenyl)butyramide from the corresponding racemic alcohols. The results showed that out of eleven commercially available lipase preparations, two enzyme preparations (Lipase A, Candida antarctica, CLEA [CAL CLEA] and Candida rugosa lipase, 62316 [CRL 62316]) act in enantioselective manner. Under optimized conditions the enantiomeric excess of both (R)- and (S)-N-(3-acetyl-4-(3-chloro-2-hydroxypropoxy)phenyl)butyramide were 99.9 and 96.8%, respectively. N-alkylation of both the (R) and (S) intermediates with isopropylamine gave enantiomerically pure (R and S)- acebutolol with a yield 68 and 72%, respectively. This study suggests a high yielding, easy and environmentally green approach to synthesize enantiopure acebutolol.
Topics: Acebutolol; Adrenergic beta-1 Receptor Antagonists; Biocatalysis; Models, Biological; Molecular Structure; Stereoisomerism; Substrate Specificity
PubMed: 25977108
DOI: 10.1002/chir.22444 -
Nephrology, Dialysis, Transplantation :... Nov 2020β-blocker (BB) dialyzability has been proposed to limit their efficacy among hemodialysis (HD) patients. We attempted to confirm this hypothesis by comparing health...
BACKGROUND
β-blocker (BB) dialyzability has been proposed to limit their efficacy among hemodialysis (HD) patients. We attempted to confirm this hypothesis by comparing health outcomes associated with the initiation of dialyzable or nondialyzable BBs in a nationwide cohort of HD patients.
METHODS
We created a prospective cohort study of 15 699 HD patients who initiated dialyzable BBs (atenolol, acebutolol, metoprolol and bisoprolol) and 20 904 hemodialysis patients who initiated nondialyzable BBs (betaxolol, carvedilol and propranolol) between 2004 and 2011 in Taiwan healthcare. We compared the risk of all-cause mortality and major adverse cardiovascular events (MACEs, a composite of the acute coronary syndrome, ischemic stroke and heart failure) between users of dialyzable versus nondialyzable BBs during a 2-year follow-up.
RESULTS
New users of dialyzable BBs were younger, more often men, with diabetes mellitus, hypertension and hyperlipidemia compared with users of nondialyzable BBs. Compared with nondialyzable BBs, initiation of dialyzable BBs was associated with lower all-cause mortality {hazard ratio [HR] 0.82 [95% confidence interval (CI) 0.75-0.88]} and lower risk of MACEs [HR 0.89 (95% CI 0.84-0.93)]. Results were confirmed in subgroup analyses, censoring at BB discontinuation or switch, after 1:1 propensity score matching, reclassifying bisoprolol or excluding bisoprolol/carvedilol users.
CONCLUSIONS
This study does not offer support for the hypothesis that the dialyzability of BBs reduces their efficacy in HD patients.
Topics: Adrenergic beta-Antagonists; Cardiovascular Diseases; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prognosis; Prospective Studies; Renal Dialysis; Survival Rate; Taiwan
PubMed: 32719861
DOI: 10.1093/ndt/gfaa058 -
Critical Care (London, England) Jun 2021β-adrenergic antagonists (BAAs) are used to treat cardiovascular disease such as ischemic heart disease, congestive heart failure, dysrhythmias, and hypertension....
BACKGROUND
β-adrenergic antagonists (BAAs) are used to treat cardiovascular disease such as ischemic heart disease, congestive heart failure, dysrhythmias, and hypertension. Poisoning from BAAs can lead to severe morbidity and mortality. We aimed to determine the utility of extracorporeal treatments (ECTRs) in BAAs poisoning.
METHODS
We conducted systematic reviews of the literature, screened studies, extracted data, and summarized findings following published EXTRIP methods.
RESULTS
A total of 76 studies (4 in vitro and 2 animal experiments, 1 pharmacokinetic simulation study, 37 pharmacokinetic studies on patients with end-stage kidney disease, and 32 case reports or case series) met inclusion criteria. Toxicokinetic or pharmacokinetic data were available on 334 patients (including 73 for atenolol, 54 for propranolol, and 17 for sotalol). For intermittent hemodialysis, atenolol, nadolol, practolol, and sotalol were assessed as dialyzable; acebutolol, bisoprolol, and metipranolol were assessed as moderately dialyzable; metoprolol and talinolol were considered slightly dialyzable; and betaxolol, carvedilol, labetalol, mepindolol, propranolol, and timolol were considered not dialyzable. Data were available for clinical analysis on 37 BAA poisoned patients (including 9 patients for atenolol, 9 for propranolol, and 9 for sotalol), and no reliable comparison between the ECTR cohort and historical controls treated with standard care alone could be performed. The EXTRIP workgroup recommends against using ECTR for patients severely poisoned with propranolol (strong recommendation, very low quality evidence). The workgroup offered no recommendation for ECTR in patients severely poisoned with atenolol or sotalol because of apparent balance of risks and benefits, except for impaired kidney function in which ECTR is suggested (weak recommendation, very low quality of evidence). Indications for ECTR in patients with impaired kidney function include refractory bradycardia and hypotension for atenolol or sotalol poisoning, and recurrent torsade de pointes for sotalol. Although other BAAs were considered dialyzable, clinical data were too limited to develop recommendations.
CONCLUSIONS
BAAs have different properties affecting their removal by ECTR. The EXTRIP workgroup assessed propranolol as non-dialyzable. Atenolol and sotalol were assessed as dialyzable in patients with kidney impairment, and the workgroup suggests ECTR in patients severely poisoned with these drugs when aforementioned indications are present.
Topics: Adrenergic beta-Antagonists; Consensus; Drug Overdose; Extracorporeal Membrane Oxygenation; Humans
PubMed: 34112223
DOI: 10.1186/s13054-021-03585-7 -
La Tunisie Medicale Feb 2020Cardiac arrest (CA) is a public health problem, with various etiologies and a fatal issue in 90-95% of cases. Toxin-induced cardiac arrests (TICA) are poorly described....
BACKGROUND
Cardiac arrest (CA) is a public health problem, with various etiologies and a fatal issue in 90-95% of cases. Toxin-induced cardiac arrests (TICA) are poorly described. Scarcity of national data prompted us to carry-out this study.
AIM
To determine TICA frequency in a Tunisian reference center in toxicology and its hospital prognosis, and to describe its clinical and therapeutic aspects Methods : Data were collected retrospectively over an 8-years period. We included patients admitted for post-CA care with highly suspected or confirmed TICA. Clinical and toxicological data were recorded.
RESULTS
We recorded 21 cases of TICA, which represented 48.8% of CA. A single toxic agent was incriminated in 90% of cases. Main causative agents identified in our series were pesticides and betablockers: chloralosed (n = 6), carbamate inhibitor of cholinesterase (n = 5), acebutolol (n = 4) and organophosphate (n = 2). One case of opiates and cocaine poisoning was reported. Median duration of "no flow" was 0 minutes. Mean duration of "low flow" was 13.74±9.15 minutes. An initial shockable rhythm was noted only in three patients. Mortality rate was 76% (16/21). Four of the five survivors had a Cerebral Performance Category Scale (CPC) 1, only one patient survived with a CPC 3. Factors associated with mortality were : the duration of "low flow" (p=0.02) and APACHE II score (p=0.014). APACHE II≥29 was the only independent factor (OR=2.0, 95%CI [1.07;3.71]).
CONCLUSION
TICA were most frequently provoked by pesticides, mortality was high and was independently predicted by APACHE II score.
Topics: Adrenergic beta-Antagonists; Cardiotoxicity; Cocaine; Drug-Related Side Effects and Adverse Reactions; Heart Arrest; Hospital Mortality; Hospitalization; Humans; Incidence; Mortality; Organophosphates; Pesticides; Retrospective Studies; Risk Factors; Toxins, Biological; Treatment Outcome; Tunisia
PubMed: 32395801
DOI: No ID Found -
Archiv Der Pharmazie Sep 2016The structure-activity relationships of 13 analogs of aryloxyaminopropanol type derived from 2-hydroxyphenylethanone as potential β-blockers are described. The...
The structure-activity relationships of 13 analogs of aryloxyaminopropanol type derived from 2-hydroxyphenylethanone as potential β-blockers are described. The synthesized compounds possess an isopropyl or a tert-butyl group in the hydrophilic part of the molecule and an alkoxymethyl substitution in the lipophilic moiety. The target compounds were prepared by an established four-step method and their structures were confirmed by interpretation of their UV, IR, (1) H NMR and (13) C NMR spectra, and by elemental analysis. The β-adrenolytic efficacy of the prepared racemic compounds was determined on isolated guinea pig atria (β1 ) and trachea (β2 ) and expressed as pA2 values against isoprenaline tachycardia. The assumed cardioselectivity was expressed as β1 /β2 ratio and the values of compounds with an alkoxy group (CH3 O, iC3 H5 O, C5 H11 O, CH2 CHCH2 O, CH3 OCH2 CH2 O) in the lipophilic part and with tert-butyl in the hydrophilic part of the molecule were found to be comparable or higher than those of the standards acebutolol and celiprolol. All evaluated substances at a concentration of 10(-7) mol/dm(3) showed also negative chronotropic effects.
Topics: Acebutolol; Adrenergic beta-Antagonists; Animals; Celiprolol; Guinea Pigs; Heart Atria; Heart Rate; Histamine; Isoproterenol; Propanolamines; Structure-Activity Relationship; Trachea
PubMed: 27417385
DOI: 10.1002/ardp.201600136 -
Journal of AOAC International 2015Two therapeutically active compounds from the group of β-blockers, acebutolol (AC) and alprenolol (AL), in solid form were subjected to ionizing radiation emitted by a...
Two therapeutically active compounds from the group of β-blockers, acebutolol (AC) and alprenolol (AL), in solid form were subjected to ionizing radiation emitted by a beam of high energy electrons from an accelerator with a standard sterilization dose of 25 kGy and in higher doses of 50-400 kGy. The effects of irradiation were detected by chromatographic methods (TLC, HPLC) and a hyphenated method (HPLC/MS/MS). No significant changes in the physicochemical properties of both compounds studied irradiated with 25 kGy were noted, but upon irradiation with the highest dose (400 kGy) the loss of AC and AL content determined by HPLC was 2.79 and 9.12%, respectively. The product of AC decomposition and the two products of AL decomposition were separated and identified by HPLC/MS/MS. It has been established that radiodegradation of AC and AL takes place by oxidation, leading to formation of the products of radiolysis, most probably alcohol derivatives of the β-blockers studied. The additional product that appears on radiodegradation of AL is probably formed as a result of two simultaneous reactions: oxidation and CH2 group elimination.
Topics: Acebutolol; Alprenolol; Chromatography, High Pressure Liquid; Radiation, Ionizing; Tandem Mass Spectrometry
PubMed: 25857877
DOI: 10.5740/jaoacint.14-096