STEREOSPECIFIC EVALUATION OF SOTALOL PHARMACOKINETICS IN A RAT MODEL - EVIDENCE SUGGESTING AN ENANTIOMERIC INTERACTION

Sotalol (STL) is a chiral beta-adrenergic blocking drug, which is usef ul clinically as the racemate in treating hypertension, and is also us eful as a class III antiarrhythmic when administered as the pure S-ena ntiomer. Utilizing a stereospecific high-performance liquid chromatogr aphic (HPLC) assay, the enantiomeric disposition of STL is reported af ter administration of racemate and both pure enantiomers to a rat mode !. After administration of the racemate, enantiomers of STL had simila r plasma concentration-time profiles. Following administration of the pure S-enantiomer of STL, however, systemic clearance was significantl y reduced; R-STL disposition after pure enantiomer administration was not significantly altered. Changes in systemic clearance of S-STL afte r either racemate or enantiomer dosing were explained by corresponding changes in renal clearance. Renal clearance values of S-STL were sign ificantly reduced from 33.7 +/- 6.0 to 28.9 +/- 5.6 ml min(-1)kg(-1) f or administration as racemate and pure enantiomer, respectively. As cl earance of STL approximates reported values of renal blood flow, renal perfusion changes caused by the beta-blocking effects of R-STL may ex plain changes in S-STL disposition. It is suggested that dosing of STL as either racemate or pure enantiomer, depending on the clinical indi cation for use, may result in significantly altered enantiomer disposi tion.