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

The pharmacokinetics of enantiomers of pimobendan and their demethylat ed metabolites in plasma and red cells were studied in 8 normal health y volunteers. After racemic pimobendan 5 mg IV, the plasma concentrati on-time curve followed a two-compartment open-model with elimination h alf-lives of 1.81h and 1.86 h for (+)- and (-)-pimobendan, respectivel y. 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.k g(-1) for (+)- and (-)-pimobendan, respectively. Plasma protein bindin g (n = 3) of (+)-, (-)-pimobendan, (+)- and (-)-demethylated metabolit es was 97.6, 97.6, 92.2 and 92.5%, respectively. The plasma concentrat ion-time curve also followed a two-compartment open model after oral a dministration of 7.5 mg racemic pimobendan. The absolute bioavailabili ties 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), respec tively. The (+)- and (-)-pimobendan concentrations in red cells were d etermined and their pharmacokinetics were estimated using red blood ce ll 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 elevate d. The volume of distribution of the central compartment of (-)-pimobe ndan in red cell was significantly smaller than that: of (+)-pimobenda n. (0.24 vs. 0.421.kg(-1).) Similar phenomena were found after IV admi nistration. These all indicated stereoselective partitioning or distri bution of (-)-pimobendan into red cells. Since the elimination half-li fe 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 stere oselective distribution of (-)-pimobendan into the red blood cells. Th is stereoselective property of the (-)isomer may be the explanation of a previous report that (-)-pimobendan produced a 1.5-times larger con tractile force in detergent-skinned preparations of cardiac muscle fro m guinea pig and dog than the (+)-isomer.