Amlodipine dynamic effects and myocardial pharmacokinetics in the isolated and perfused guinea-pig heart.

Abstract

Myocardial dynamic effects and pharmacokinetics of amlodipine were studied in the isolated retrogradely perfused and spontaneously beating guinea-pig heart. Pharmacokinetic analysis of drug accumulation showed one-compartment characteristics with an half-life of 76 min. Whereas disposition exhibited two-compartment characteristics with phasic half-lives of 25 and 174 min., respectively. Myocardial drug accumulation was increased by 600 times at steady-state compared to the perfusion liquid. Dynamic effect parameters were studied during increasing amlodipine concentrations from 0.16 to 220 nM. Dynamic steady-states developed within 20 min. Coronary flow-rate increased with an Emax of 119% and an EC50 of 1.2 x 10(-8) M. Amlodipine produced inhibitory effects on contraction amplitude and velocities of contraction and relaxation. Observed Emax-values and curve-fitted EC50-values were: 97, 97 and 94% and 1.10(-8), 7.7 x 10(-9) and 2.1 x 10(-8) M, respectively. Heart frequency was not changed. Oxygen consumption increased markedly to a maximum of 44% at 3 x 10(-8) M amlodipine and then decreased to nearly initial values. The frequency-corrected QT-interval decreased to a maximal extent of 20% at the three highest concentrations. Myocardial efficiency expressed as the ratio of contraction velocity times frequency to oxygen consumption exhibited a progressive decline to about 2% of initial values. The PQ-interval was not changed and the QRS-interval showed only a small but significant decrease at the highest amlodipine concentration. No arrythmogenic effects were observed. The study demonstrated a very slow accumulation and disposition of amlodipine in the guinea-pig heart with a steady-state myocardial drug concentrating accumulation of 600 times. Marked increase in coronary flow-rate and oxygen consumption accompanied by a progressive negative inotropic effect were observed.