PLASMA AND RED-BLOOD-CELL PHARMACOKINETICS OF PIMOBENDAN ENANTIOMERS IN HEALTHY CHINESE

The pharmacokinetics of enantiomers of pimobendan and their demethylated metabolites in plasma and red cells were studied in 8 normal healthy volunteers. After racemic pimobendan 5 mg IV, the plasma concentration-time curve followed a two-compartment open-model with elimination half-lives of 1.81h and 1.86 h for (+)- and (-)-pimobendan, respectively. The clearances and volumes of distribution postequilibrium were 13.5 ml.min(-1).kg(-1), 14.4 ml.min(-1).kg(-1); 1.741. kg(-1) and 2.341.kg(-1) for (+)- and (-)-pimobendan, respectively. Plasma protein binding (n = 3) of (+)-, (-)-pimobendan, (+)- and (-)-demethylated metabolites was 97.6, 97.6, 92.2 and 92.5%, respectively. The plasma concentration-time curve also followed a two-compartment open model after oral administration of 7.5 mg racemic pimobendan. The absolute bioavailabilities of (+)- and (-)-pimobendan were 0.51 and 0.55. Peak levels of (+)and (-)-pimobendan, both at 1.2h, were 15.8 and 16.8 ng.ml(-1), respectively. The (+)- and (-)-pimobendan concentrations in red cells were determined and their pharmacokinetics were estimated using red blood cell data. Interesting phenomena were observed: the peak concentrations of (+)- and (-)-pimobendan in red blood cells were about 5.5- and 9.2-times higher than in plasma, and the AUCs were correspondingly elevated. The volume of distribution of the central compartment of (-)-pimobendan in red cell was significantly smaller than that: of (+)-pimobendan. (0.24 vs. 0.421.kg(-1).) Similar phenomena were found after IV administration. These all indicated stereoselective partitioning or distribution of (-)-pimobendan into red cells. Since the elimination half-life of (+)- and (-)-pimobendan in red cells was similar (3.07 vs 2.97 h), the highly significant difference in clearance between (+)- and (-)-pimobendan (3.7 vs 2.3 ml.min(-1).kg(-1)) was solely due to the stereoselective distribution of (-)-pimobendan into the red blood cells. This stereoselective property of the (-)isomer may be the explanation of a previous report that (-)-pimobendan produced a 1.5-times larger contractile force in detergent-skinned preparations of cardiac muscle from guinea pig and dog than the (+)-isomer.