Sotalol Chiral Separation by Capillary Electrophoresis

Hancu, Gabriel; Sămărghiţan, Claudia; Rusu, Aura; Mircia, Eleonora

doi:10.4067/s0717-97072014000300007

Cited by 8 publications

(4 citation statements)

References 9 publications

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“…Like many other drugs in aqueous solution, d-sotalol can exist in several protonation states depending on solution pH and other factors, such as proximity to specific protein residues. Data from the literature indicate that aqueous p K a -values for d-sotalol are 8.3 and 9.8 attributed to deprotonation of sulfonamide and secondary ammonium functionalities, respectively (Foster and Carr, 1992 ; Hancu et al, 2014 ). This indicates that at physiological pH 7.4, SotC is the predominant form (around 89%), while deprotonation of the sulfonamide functionality leads to a second dominant SotZ form (around 11%).…”

Section: Resultsmentioning

confidence: 99%

Digging into Lipid Membrane Permeation for Cardiac Ion Channel Blocker d-Sotalol with All-Atom Simulations

et al. 2018

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Interactions of drug molecules with lipid membranes play crucial role in their accessibility of cellular targets and can be an important predictor of their therapeutic and safety profiles. Very little is known about spatial localization of various drugs in the lipid bilayers, their active form (ionization state) or translocation rates and therefore potency to bind to different sites in membrane proteins. All-atom molecular simulations may help to map drug partitioning kinetics and thermodynamics, thus providing in-depth assessment of drug lipophilicity. As a proof of principle, we evaluated extensively lipid membrane partitioning of d-sotalol, well-known blocker of a cardiac potassium channel Kv11.1 encoded by the hERG gene, with reported substantial proclivity for arrhythmogenesis. We developed the positively charged (cationic) and neutral d-sotalol models, compatible with the biomolecular CHARMM force field, and subjected them to all-atom molecular dynamics (MD) simulations of drug partitioning through hydrated lipid membranes, aiming to elucidate thermodynamics and kinetics of their translocation and thus putative propensities for hydrophobic and aqueous hERG access. We found that only a neutral form of d-sotalol accumulates in the membrane interior and can move across the bilayer within millisecond time scale, and can be relevant to a lipophilic channel access. The computed water-membrane partitioning coefficient for this form is in good agreement with experiment. There is a large energetic barrier for a cationic form of the drug, dominant in water, to cross the membrane, resulting in slow membrane translocation kinetics. However, this form of the drug can be important for an aqueous access pathway through the intracellular gate of hERG. This route will likely occur after a neutral form of a drug crosses the membrane and subsequently re-protonates. Our study serves to demonstrate a first step toward a framework for multi-scale in silico safety pharmacology, and identifies some of the challenges that lie therein.

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Section: Resultsmentioning

confidence: 99%

Digging into Lipid Membrane Permeation for Cardiac Ion Channel Blocker d-Sotalol with All-Atom Simulations

et al. 2018

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“…An exception to this rule is sotalol, (RS)-N-{4-[1-hydroxy-2-(propan-2-ylamino)ethyl]phenyl} methanesulfonamide. It is a hydrophilic non-selective β-blocker, characterized more often as a class-III antiarrhythmic agent [22] . It has a phenylethanolamine structure and its asymmetric carbon atom is located in an ethanolamine type side chain (fig.…”

mentioning

confidence: 99%

“…Because of its enantioselectivity, sotalol mechanism of action is divided between two antiarrhythmic drug classes. The R(-)-sotalol has both β-blocking (class-II antiarrhythmic agent) and potassium channel blocking activity (class-III antiarrhythmic agent), while the S(+)-sotalol has only the potassium channel blocking activity and its affinity towards β-adrenergic receptor is 30-60 times lower [22] . Hence, R(-)-enantiomer would cause decrease in heart rate and a limited reduction in the force of contraction of the heart.…”

mentioning

confidence: 99%

Enantioselective Conversion of Racemic Sotalol to R(-)-Sotalol by Lipase AP6

Swetha¹,

Vijitha²,

Veeresham³

2018

pharmaceutical-sciences

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Most pharmaceutical compounds have asymmetric nature and are optically active. Compounds with one asymmetric centre (chiral centre) would exhibit two enantiomeric forms and among them one is pharmacologically active (eutomer) while the other one contributed side effects or toxic effects or totally inert (distomer) [1] . Hence, current interest is towards development and administration of eutomer instead of its racemic mixture to improve therapeutic efficacy and reduce the unwanted effects due to the distomer [2] . Biocatalysts have excellent selectivity under mild reaction conditions [2] and hence in this study various whole-cell microorganisms like Bacillus subtilis [3] , Escherichia coli [4] , Pseudomonas putida [5] , Sphingomonas paucimobilis [6] , Rhodococcus erythropolis [7] , Streptomyces halstedii [8] , Aspergillus niger [9] , Candida parapsilosis [10] , Geotrichum candida [11] , Rhizopus oryzae [12] , Cunninghamella elegans [13] and Cunninghamella blakesleeana [14] were employed as biocatalysts for the stereo inversion of racemic sotalol to its active enantiomer. However, a limitation for using whole-cell microorganisms as biocatalysts is reduced stereo selectivity due to competition between multiple enzymes of the microorganism for the same substrate [15] . The use of isolated pure enzymes with suitable cofactors as biocatalysts would help overcome this limitation of using whole-cell microorganisms [16] and the reactions catalysed by pure enzymes also serves some other advantages like they are highly selective under mild conditions, more catalytic in nature and environmentally benign [2] . Lipases have great versatility in catalysing different reactions like aminolysis, esterification, transesterification and interesterification. The means followed by lipases to catalyse these reactions can be described as a ping-pong bi-bi mechanism. Accordingly, first step involves nucleophilic attack on the carbonyl group of a drug, which results in acyl-

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“…SOT is almost completely absorbed after oral administration and is excreted almost entirely in urine as an unchanged drug with 50 to 80 % of a dose being excreted in 24 hrs; less than 10 % is eliminated in the faeces [2]. SOT has been quantified using several different analytical methodologies including: chromatography [3][4][5][6][7][8], fluorescence [9], capillary zone electrophoresis [10,11], and electrochemical (voltammetry) [1,[12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Incorporation of Tetrazolium Blue (TB)/Gold Nanoparticles (GNPs) into Carbon Paste Electrode: Application as an Electrochemical Sensor for the Sensitive and Selective Determination of Sotalol in Micellar Medium

et al. 2017

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The electrochemical oxidation of Sotalol (SOT) based on Tetrazolium Blue (TB)/gold nanoparticles (GNPs)‐modified carbon paste electrodes (CPE) have been studied in the presence of sodium lauryl sulphate (SLS). Cyclic voltammetry (CV), differential pulse voltammetry (DPV), chronoamperometry and electrochemical impedance spectroscopy (EIS) techniques have all been utilized within this study. GNPs and TB have a synergetic effect‐giving rise to highly improved electrochemical responses and provide an advantageous platform for the basis of an electrochemical sensor with excellent performance. The experimental parameters, electrodeposition time, pH and scan rate have all been examined and optimized. The sensing of SOT via DPV is found to exhibit a wide linear dynamic range of 1.0×10−7–7.5×10−4 M in pH 2. LOD and LOQ were calculated and found to correspond to 2.5×10−8 M and 8.3×10−8 M, respectively. The suggested sensor has been used successfully for SOT determination in pharmaceutical samples and human urine as real samples. Satisfactory recoveries of analyte from these samples are demonstrated indicating that the suggested sensor is highly suitable for clinical analysis, quality control and a routine determination of SOT in pharmaceutical formulations.

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Sotalol Chiral Separation by Capillary Electrophoresis

Cited by 8 publications

References 9 publications

Digging into Lipid Membrane Permeation for Cardiac Ion Channel Blocker d-Sotalol with All-Atom Simulations

Digging into Lipid Membrane Permeation for Cardiac Ion Channel Blocker d-Sotalol with All-Atom Simulations

Enantioselective Conversion of Racemic Sotalol to R(-)-Sotalol by Lipase AP6

Incorporation of Tetrazolium Blue (TB)/Gold Nanoparticles (GNPs) into Carbon Paste Electrode: Application as an Electrochemical Sensor for the Sensitive and Selective Determination of Sotalol in Micellar Medium

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