Assay of negative inotropism of bepridil on isolated guinea pig left atrial myocardium by simulating constant rate of absorption and elimination

The pharmacodynamic characteristic of negative inotropic effect of bepridil on isolated guinea pig cardiac atrium was conducted by gradient perfusion with constant rate of bepridil ranging from 0-20 mumol.L-1 and inverse, simulating a fixed pharmacokinetic parameters of K(a) and K(e), respectively. A counter-clockwise hysteresis loop of negative inotropism of bepridil was presented. Fixing Cp, T, and E by pharmacokinetics/pharmacodynamics (PK/PD) non-parameter model, the hysteresis loop was collapsed in figure plotting C(e) against E. The estimated K(eo) = 0.03 +/- 0.023 h-1, an apparent T1/2 of pharmacological effect was measured, and about 80-fold as long as the pharmacokinetic T1/2. It was suggested that the long-lasting effect of bepridil was partly due to the slow elimination rate from the effect compartment.