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 useful clinically as the racemate in treating hypertension, and is also useful as a class III antiarrhythmic when administered as the pure S-enantiomer. Utilizing a stereospecific high-performance liquid chromatographic (HPLC) assay, the enantiomeric disposition of STL is reported after administration of racemate and both pure enantiomers to a rat model. After administration of the racemate, enantiomers of STL had similar plasma concentration-time profiles. Following administration of the pure S-enantiomer of STL, however, systemic clearance was significantly reduced; R-STL disposition after pure enantiomer administration was not significantly altered. Changes in systemic clearance of S-STL after either racemate or enantiomer dosing were explained by corresponding changes in renal clearance. Renal clearance values of S-STL were significantly reduced from 33.7 +/- 6.0 to 28.9 +/- 5.6 ml min-1 kg-1 for administration as racemate and pure enantiomer, respectively. As clearance of STL approximates reported values of renal blood flow, renal perfusion changes caused by the beta-blocking effects of R-STL may explain changes in S-STL disposition. It is suggested that dosing of STL as either racemate or pure enantiomer, depending on the clinical indication for use, may result in significantly altered enantiomer disposition.
Carr
R A
RA
Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Pasutto
F M
FM
Foster
R T
RT
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013015:Sotalol / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D013015:Sotalol