Stereoselective Pharmacokinetics of Bisoprolol After Intravenous and Oral Administration in Beagle Dogs

Abstract

The stereoselective pharmacokinetics of bisoprolol, a highly β1-selective adrenoceptor blocking agent, was studied in dogs. After intravenous and oral administration of the racemate, there was a difference in the plasma concentration between S(−)- and R(+)-bisoprolol. The area under the curve (AUC) of concentration versus time of S(−)-bisoprolol was ∼1.5 times higher than that of R(+)-bisoprolol, and the elimination half–life of S(−)-bisoprolol was ∼1.4 times longer than that of R(+)-bisoprolol. However, no differences were observed in the volume of distribution, absolute bioavailability, and renal clearance between the two enantiomers. The plasma protein binding of S(−)-bisoprolol was also the same as that of the R(−)-isomer. No chiral inversion or enantiomer–enantiomer interaction was observed, when enantiomers were solely administered via the intravenous route. The comparison of the oxidative metabolic rate of two enantiomers using dog liver microsomes demonstrated that the metabolite was more slowly formed from S(−)- than from R(+)-bisoprolol. Consequently, we concluded that the stereoselective difference in the metabolic clearance between S(−)- and R(+)-bisoprolol caused the difference in the disposition of bisoprolol enantiomers.