COMPARATIVE PHARMACOKINETIC AND PHARMACODYNAMIC PROPERTIES OF ORAL AND INTRAVENOUS (-SOTALOL IN HEALTHY-VOLUNTEERS())

The pharmacokinetic and pharmacodynamic properties of (+)-sotalol (BMY -5763) were studied to analyse the relationship between plasma concent ration and QT, prolongation in healthy male volunteers given single or al doses of 50, 100, 200 and 300 mg, repeated oral doses of 200 mg twi ce daily for 6.5 days, and single intravenous doses of 1.0 and 1.5 mg kg(-1). The plasma concentration of (+)-sotalol peaked about 3 h after oral administration and declined with a half-life of 7.9-9.7 h. The C -max and AUC showed dose-related increases, while the urinary recovery as the unchanged form remained constant (66-68% of the dose). During repeated oral administration the plasma concentration of (+)-sotalol r eached almost a steady state on the 3rd day and there was no change in renal clearance of(+)-sotalol measured on the 1st, 4th and 7th days. After intravenous administration, (+)-sotalol in plasma decreased biex ponentially with a terminal half-life of 7.6-8.3 h and the urinary rec overy as unchanged drug amounted to 84-88% of the dose. The increase i n QT interval was significant after a single oral administration excep t for the lowest dose, and regression analysis revealed a significant correlation between QT, interval and concentration of (+)-sotalol in p lasma. The same correlation was evident with repeated oral doses on th e 1st, 4th and 7th days. In the case of single intravenous administrat ions of (+)-sotalol, a combined pharmacokinetic-pharmacodynamic model was attempted by assuming an effect compartment. This analysis was sho wn to be effective to adjust the lag of effect behind a rapid change i n plasma concentration which occurred in the early distributive phase because there was no evidence that the metabolite made any significant contribution to the effect of (+)-sotalol.