Comparability of the Electrophysiologic Responses and Plasma and Myocardial Tissue Concentrations of Sotalol and its d Stereoisomer in the Dog

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Abstract
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 ECG alterations and venous blood samples were withdrawn on the 1st, 3rd, 7th, and 14th day of drug administration.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. In acute experiments, there were no differences between the distributive and washout phases of either drug under the short-term conditions of the experiments. No preferential uptake of either agent in atrial, ventricular, or septal areas of the myocardium was demonstrable.