Comparability of the electrophysiologic responses and plasma and myocardial tissue concentrations of sotalol and its d stereoisomer in the dog.

The relative plasma, myocardial, and skeletal muscle concentrations as well as activities of racemic and d-sotalol were assessed in both anesthetized and conscious dogs. In acute anesthetized experiments, the agents were infused i.v. over a 15-min interval at doses of 1 and 4 mg/kg. Arterial blood samples and punch biopsy specimens from the left ventricular myocardium and skeletal muscle (gastrocnemius) were taken at the completion of each infusion and at periodic intervals for the ensuing 3 h. The drugs were also administered over a 2-week dosing interval to conscious dogs at a dose of 5 mg/kg given twice daily. ECG alterations and venous blood samples were withdrawn on the 1st, 3rd, 7th and 14th day of drug administration. Myocardial and skeletal muscle samples were taken at killing on day 14. In anesthetized dogs, both forms of sotalol decreased heart rate, lowered arterial pressure, prolonged ventricular refractoriness, and caused measurable increases in the PR, QT, and QTc intervals in the absence of any effect on QRS duration. Similar effects on heart rate and QTc and lack of influence on the PR and QRS interval were observed in conscious animals. Tissue drug concentrations were closely correlated with plasma drug levels. Comparable mean steady-state tissue/plasma ratios of 2.26-2.94 were attained immediately following acute i.v. drug infusions. These were larger than those observed following chronic oral drug administration for 14 days. The data, however, clearly demonstrated the equivalence of the plasma and myocardial drug levels obtained in dogs following i.v. infusion of 1 mg/kg or oral administration of 5 mg/kg of dl- or d-sotalol.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of encainide and metabolites in plasma and urine by high-performance liquid chromatography.

A high performance liquid chromatography (HPLC) method for the quantification of encainide (4-methoxy-2'-[2-(1-methyl-2-piperidinyl)-ethyl]benzanilide hydrochloride) in plasma and urine has been developed and validated. Encainide and two metabolites, the O-demethyl (ODE) and 3-methoxy-O-demethyl (MODE) congeners of the drug, can be quantified simultaneously in plasma and urine by this procedure. The compounds are extracted from buffered plasma (pH 8.5) using N-butyl chloride containing 5% (vol/vol) isopropyl alcohol. The compounds are then separated on a silica column using ethanol:water:methanesulfonic acid, 500/60/0.2 (vol/vol/vol) as the mobile phase and quantified by measuring their UV absorbance at 254 nm. The lower limit of detection for the analytes was 5 ng/ml in plasma and 25 ng/ml in urine. The method was linear from 5 to 5,000 ng/ml for plasma and 25 to 5,000 ng/ml for urine. The intra-assay precision of the method for encainide, ODE, and MODE in plasma and urine ranged from 2 to 8% RSD depending upon concentration. The inter-assay precision of the method was less than 6% for the three analytes per ml of plasma and urine. Absolute recovery of the analytes from plasma ranged from 82 to 92%, while recoveries from urine ranged from 83 to 99%. The analytes were shown to be stable in frozen plasma and urine for up to 52 weeks.

Liquid chromatographic determination of sotalol in plasma and urine employing solid-phase extraction and fluorescence detection.

A liquid chromatographic method using a solid-phase extraction procedure for the quantification of sotalol in plasma and urine is described. Sotalol is eluted from an extraction column with ethyl acetate-acetonitrile (1:2) and, after separation by reversed-phase high-performance liquid chromatography on a mu Bondapak C18 column, is quantified by fluorescence detection at excitation and emission wavelengths of 240 and 310 nm, respectively. The method has been demonstrated to be linear over the concentration ranges 10-6000 ng/ml in plasma and 0.5-100 micrograms/ml in urine. Mean inter-assay accuracy of the method for plasma ranged from 93 to 100% and for urine from 102 to 114%; precision ranged from 0.5 to 1.6% for plasma over a concentration range of 200-4000 ng/ml and for urine from 0.7 to 2.0% at concentrations of 2-50 micrograms/ml. Mass spectrometry confirmed the presence of sotalol in isolated chromatographic fractions of plasma and urine extracts from subjects given sotalol orally.

Comparative beta-blocking activities and electrophysiologic actions of racemic sotalol and its optical isomers in anesthetized dogs.

The relative activities of d-, 1- and racemic-sotalol were studied in two series of anesthetized dogs. Estimates of relative beta-adrenergic blocking potency were based upon the ability of the compounds to antagonize isoproterenol-elicited increases in heart rate and decreases in diastolic blood pressure. On a molar basis, d-sotalol displayed 1/12-1/14th and 1-sotalol 1.6-3.2 X the potency of the racemic parent drug as beta-antagonists. His bundle electrogram (HBE) measurements, surface ECG recordings and the extra stimulus technique at a constant pacing cycle length were utilized to assess the comparative effects of sotalol and its optical isomers on cardiac conduction and refractoriness. At i.v. doses spanning equiactive beta-blocking levels, d- (1, 4, 16 mg X kg-1), 1- (0.25, 1, 4 mg X kg-1) or dl-sotalol (0.5, 2, 8 mg X kg-1) caused dose-dependent increases in ventricular and, to an even greater extent, atrial refractoriness. The mean plasma drug concentrations (Cp) attained with these doses were: d-sotalol 9.5, 44 and 267 nmol X l-1; 1-sotalol 9.6, 16 and 66 nmol X l-1; and dl-sotalol 5.4, 23 and 106 nmol X l-1. The relative mg potency from greatest to least was 1-sotalol greater than dl-sotalol greater than d-sotalol in prolonging the ventricular effective refractory period (V-ERP); the mean increases above control at the highest dose of each were 58 +/- 4, 47 +/- 6 and 38 +/- 3 ms, respectively. At those same dose levels, atrial refractoriness (A-ERP) was maximally elevated 49 +/- 11, 82 +/- 5 and 104 +/- 10 ms by 1-, dl- and d-sotalol, respectively. These increases in refractoriness occurred without alterations in atrial, His-Purkinje or ventricular conduction velocity; however, all three forms of sotalol significantly reduced AV nodal conduction. At the dose multiples studied, the effects on this variable (AH interval) were greatest following 1-sotalol (20-60 ms) or racemic sotalol (20-57 ms) and least following the d-isomer (7-43 ms). The profile of effects observed with d-sotalol is that of an agent with Class III electrophysiologic effects and weak beta-adrenergic blocking properties.

Determination of bucindolol and its major metabolites in plasma by capillary gas chromatography-mass spectrometry.

A method for determining bucindolol, a deuterated analogue and two metabolites in plasma samples is described. Analytes are obtained from plasma by liquid extraction of 1 ml of plasma at pH 10.5 with 7 ml of peroxide-free ether-hexane (4:1). Following derivatization with 50 microliters of N-methyl-N-trimethylsilyl trifluoroacetamide-pyridine (1:1) for 20 min at 65 degrees C the samples are analyzed by capillary column gas chromatography-mass spectrometry with selected-ion monitoring. Quantification is linear over the range 2-500 ng/ml. Single-day precision was typically 6.2% or better for bucindolol and 13% or better for the metabolites.

Synthesis of 3,4-dihydro-4-oxothieno[2,3-d]pyrimidine-2-carboxylates, a new series of orally active antiallergy agents.

A series of novel 3,4-dihydro-4-oxothieno[2,3-d]pyrimidine-2-carboxylic acid derivatives has been prepared and tested for antiallergenic activity. Members of the series, including both carboxylic acid salts and esters, have been found to exhibit oral activity in the rat passive cutaneous anaphylaxis (PCA) test. Activity is optimized by H or CH3 substitution at the 5 position and lower alkyl groups at the 6 position. Ethyl 6-ethyl-3,4-dihydro-4-oxothieno-[2,3-d]pyrimidine-2-carboxylate and 3,4-dihydro-5-methyl-6-(2-methylpropyl)-4-oxothieno[2,3-d]pyrimidine-2-carboxylic acid dipotassium salt were the most potent of the esters and salts, respectively. Such compounds have been shown to have a duration of action of up to 4 h in the PCA test and to inhibit both histamine release from rat peritoneal mast cells in vitro and allergen-induced bronchospasm in the rat lung.