Resolution, absolute configuration, and antiarrhythmic properties of the enantiomers of disopyramide, 4-(diisopropylamino)-2-(2-pyridyl)-2-phenylbutyramide

Burke, Terrence R.; Nelson, Wendel L.; Mangion, M.; Hite, G.; Mokler, Corwin M.; Ruenitz, Peter C.

doi:10.1021/jm00183a015

Cited by 37 publications

(6 citation statements)

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“…Interestingly, total clearance of each of the isolated enantiomers is similar but the S‐enantiomer is cleared significantly more slowly when the racemate is given [42]. R‐disopyramide and S‐disopyramide have very similar activities with respect to prolonging the effective refractory period [43]. Consequently, while there are assays available to determine the enantiomers of disopyramide [44], the lack of stereospecificity of commonly used TDM assays would not appear to be a major concern S‐disopyramide is 3–4 times more potent than R‐disopyramide with respect to anticholinergic activity [45].…”

Section: Class I Antiarrhythmic Agentsmentioning

confidence: 99%

Therapeutic drug monitoring: antiarrhythmic drugs

Campbell

Williams

1998

Brit J Clinical Pharma

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Antiarrhythmic agents are traditionally classified according to Vaughan Williams into four classes of action. Class I antiarrhythmic agents include most of the drugs traditionally thought of as antiarrhythmics, and have as a common action, blockade of the fast‐inward sodium channel on myocardium. These agents have a very significant toxicity, and while they are being used less, therapeutic drug monitoring (TDM) does significantly increase the safety with which they can be administered. Class II agents are antisympathetic drugs, particularly the β‐adrenoceptor blockers. These are generally safe agents which do not normally require TDM. Class III antiarrhythmic agents include sotalol and amiodarone. TDM can be useful in the case of amiodarone to monitor compliance and toxicity but is generally of little value for sotalol. Class IV antiarrhythmic drugs are the calcium channel blockers verapamil and diltiazem. These are normally monitored by haemodynamic effects, rather than using TDM. Other agents which do not fall neatly into the Vaughan Williams classification include digoxin and perhexiline. TDM is very useful for monitoring the administration (and particularly the safety) of both of these agents.

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Section: Class I Antiarrhythmic Agentsmentioning

confidence: 99%

Therapeutic drug monitoring: antiarrhythmic drugs

Campbell

Williams

1998

Brit J Clinical Pharma

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“…Disopyramide base was extracted from Rythmodan capsules (Roussel Laboratories Ltd, UK). S-Disopyramide was separated by fractional crystallization of the disopyramide bitartrate salts (Burke et al 1980). The test compounds were dissolved in sterile 0.9% NaCl (saline) before use.…”

Section: Chemicalsmentioning

confidence: 99%

Comparative Drug Exsorption in the Perfused Rat Intestine

Huang

1990

Journal of Pharmacy and Pharmacology

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The factors affecting drug exsorption into the gastrointestinal tract are uncertain. In this study, the intestinal clearance (CLi) of compounds which vary in their lipophilicity, serum protein binding, molecular weight and ionic charge at physiological pH, has been measured. Male Sprague-Dawley rats with ligated bile ducts were infused with the test compounds through the jugular vein. The small intestine was intubated and perfused with Tyrode solution at 20 mL h-1. The CLi of the compounds investigated (urea, polyethylene glycol, inulin, albumin, dextran, barbituric acid, salicylic acid, thiobarbital, thiopental, thioseconal, theophylline, S-disopyramide and quinidine) was determined under anaesthesia by dividing the rate of a component's appearance rate in the perfusate by its carotid arterial concentration. Serum protein binding of the compounds was determined by equilibrium dialysis. The n-octanol-water partition coefficients of the compounds were measured as indices of lipophilicity. The CLi values of dextran, albumin, inulin, polyethylene glycol and urea were 0.56, 1.03, 4.5, 4.8 and 12.0 mL h-1, respectively. The larger the molecular weight of a compound, the smaller its CLi. The molecular weight is apparently one of the major determinants of CLi. Thiobarbital, thiopental and thioseconal are compounds of similar structure with increasing lipophilicity and serum protein binding. The CLi of thiobarbital, thiopental and thioseconal was proportional to the unbound fraction in serum. The unbound clearance (CLui) of three thiobarbiturates were similar (approximately 11 mL h-1). The unbound fraction of drug in serum appears to be a factor determining their CLi. Barbituric acid and salicylic acid, two acidic compounds, showed a low CLi (less than 1 mL h-1).(ABSTRACT TRUNCATED AT 250 WORDS)

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“…However, single-crystal X-ray data of either of crystal form were not present in the Cambridge Structural Database (CSD), whereas the crystal structure of [C 21 H 30 N 3 O] + [H 2 PO 4 ] − disopyramide dihydrogen phosphate has been reported by Kawamura and Hirayama in 2011 [43]. Furthermore, X-single crystal structure of (+)-disopyramide (2R,3R)-bitartrate salt was reported in 1980 for determining the absolute configuration of disopyramide by Burke and Nelson [44], and the structure was not present in the CSD. Moreover, to the best knowledge of the authors, not much research has been carried out with respect to creating the novel salt form of DPA.…”

Section: Introductionmentioning

confidence: 99%

Crystal Structures of Antiarrhythmic Drug Disopyramide and Its Salt with Phthalic Acid

et al. 2021

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Disopyramide (DPA) is as a class IA antiarrhythmic drug and its crystallization from cyclohexane at ambient condition yields lower melting form crystals which belong to the monoclinic centrosymmetric space group P21/n, having two molecules in an asymmetric unit. Crystal structure analysis of pure DPA revealed closely associated DPA molecules aggregates via amide–amide dimer synthon through the N–H∙∙∙O hydrogen bond whereas the second amide hydrogen N–H engaged in an intramolecular N–H∙∙∙N hydrogen bond with N-nitrogen of 2-pyridine moieties. Crystallization of DPA and phthalic acid (PA) in 1: 1 stoichiometric molar ratio from acetone at ambient condition yielded block shape crystals of 1:1 DPA_PA salt. Its X-ray single crystal structure revealed the formation of salt by transfer of acidic proton from one of the carboxylic acidic groups of PA to the tertiary amino group of chain moiety (N3-nitrogen atom) of DPA molecules. DPA_PA salt crystals belong to the monoclinic centrosymmetric space group P21/n, comprising one protonated DPA and one PA¯ anion (hydrogen phthalate counterion) in an asymmetric unit and linked by N–H∙∙∙O and C–H∙∙∙O hydrogen bonds. Pure DPA and DPA_PA salt were further characterized by differential calorimetric analysis, thermal gravimetric analysis, powder x-ray diffraction and infrared spectroscopy.

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Resolution, absolute configuration, and antiarrhythmic properties of the enantiomers of disopyramide, 4-(diisopropylamino)-2-(2-pyridyl)-2-phenylbutyramide

Cited by 37 publications

References 0 publications

Therapeutic drug monitoring: antiarrhythmic drugs

Therapeutic drug monitoring: antiarrhythmic drugs

Comparative Drug Exsorption in the Perfused Rat Intestine

Crystal Structures of Antiarrhythmic Drug Disopyramide and Its Salt with Phthalic Acid

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