Pimobendan is a new inotropic agent with vasodilator properties. We have reported the pharmacokinetics of enantiomers of pimobendan in healthy humans. The present report focuses on the pharmacodynamic effect of pimobendan and a simultaneous pharmacokinetic-pharmacodynamic modeling. Eight normal healthy volunteers were studied with oral administration of 7.5 mg and i.v. administration of 5 mg of racemic pimobendan. Concentrations of enantiomers of pimobendan were determined by high performance liquid chromatography. Cardiovascular effects of pimobendan were evaluated by echocardiography. Oral pimobendan significantly reduced 29.0% and 16.5% of the left ventricle end-systolic dimension (LVESD) and end-diastolic dimension, respectively. The mean velocity of circumferential fiber shortening, ejection fraction, and fractional shortening significantly increased 105.9%, 29.8%, and 46% from their baseline values, respectively. The cardiovascular effects of i.v. pimobendan were similar but to a lesser extent. Plots of effect versus plasma concentration (Cp) showed counterclockwise hysteresis loops. A hypothetical effect compartment was established and incorporated into a sigmoid Emax model to describe the time courses of Cps of pimobendan and effects on LVESD. The maximal changes (Emax) in LVESD would be 2.60 +/- 0.51 cm and 2.30 +/- 0.13 cm as estimated from plasma data of (+)- and (-)-pimobendan, respectively. The estimated effect-site concentrations corresponding with 50% of the maximal effect (Ce50) were 6.54 +/- 1.35 and 6.64 +/- 1.35 ng/ml for (+)- and (-)-pimobendan, respectively. A simultaneous pharmacokinetic-pharmacodynamic model could be established to suppress the hysteresis loop and to predict the pharmacological effect based on Cp.