PHARMACOKINETICS AND PHARMACODYNAMICS OF ENANTIOMERS OF PIMOBENDAN INPATIENTS WITH DILATED CARDIOMYOPATHY AND CONGESTIVE-HEART-FAILURE AFTER SINGLE AND REPEATED ORAL DOSING

Pharmacokinetics and pharmacodynamics of pimobendan were studied in ei ght patients with dilated cardiomyopathy and chronic congestive heart failure after single dosing and after 2-week repeated dosing of 5 mg r acemic pimobendan. Enantiomers of pimobendan and its demethylated meta bolite in plasma and in red blood cells were measured. In the single-d ose study, the peak plasma levels of 16.3 +/- 4.0 and 17.0 +/- 3.1 ng/ ml of(+)- and (-)-pimobendan were observed at 0.9 hour after dosing. T he concentration-time curves followed a two-compartment model, with te rminal half-lives of 2.56 +/- 0.35 and 2.93 +/- 0.33 hours for (+)- an d (-)-pimobendan (p > 0.05), respectively. The oral volumes of distrib ution after equilibrium were 3.26 +/- 0.74 and 3.13 +/- 0.75 L/kg, and oral clearances were 28.6 +/- 7.0 and 21.9 +/- 4.1 ml/min/kg for (+)- and (-)-pimobendan (p > 0.05), respectively. In red blood cells, the respective (+)- and (-)-pimobendan concentrations were 5.8 and 8.4 tim es higher than those in plasma, indicating a stereoselective partition ing of drugs between plasma and red blood cells. The pharmacodynamic e ffect of pimobendan was evaluated by echocardiography. The ejection fr action, mean velocity of circumferential fiber shortening, aortic flow peak velocity, cardiac index, and stroke volume index significantly i ncreased 50% to 60%. The left ventricular end-systolic dimension, syst olic blood pressure, and diastolic blood pressure significantly decrea sed 8% to 11%. These effects lasted for more than 8 hours. In a 2-week repeated-dose study, there was no significant dose accumulation in pl asma and red blood cells. The pharmacokinetic parameters were similar to those in the single-dose study, except for significantly shorter ab sorption half-lives. The baseline levels of cardiac index and stroke v olume index were significantly higher than the baseline levels in the single-dose study. This suggests an accumulation of pharmacodynamic ef fects despite a relatively short elimination half-life.