Myocardial pharmacokinetics and pharmacodynamics of nifedipine in the isolated rabbit heart.

The myocardial accumulation and disposition pharmacokinetics of the antianginal and antihypertensive calcium-antagonistic drug nifedipine were investigated in isolated, perfused and spontaneously beating rabbit hearts. The myocardium behaved pharmacokinetically as a two-compartment system with regard to the drug. The mean half-lives of the alpha-phase of distribution and of the beta-phase of disposition were about 1.2 and 6.5 min., respectively. Perfusion with a modified Krebs-Henseleit solution containing nifedipine in a concentration of 50 ng ml-1 caused by accumulation of about 1277 ng g-1 in the myocardium at steady state. Stepwise increased concentrations of nifedipine from 3 to 60 ng ml-1 in the liquid used in perfusions for 25 min. periods produced a pronounced progressive decrease in myocardial contractility to about 8%. The heart beating frequency simultaneously decreased gradually to about 76%. The mean coronary flow rate increased initially to 135% and then gradually decreased to 94%. These effects were accompanied by a decrease to about 0.27 in the ratio of the product of contraction amplitude and frequency to the oxygen consumption, a finding that was evaluated as an expression of reduced myocardial efficiency. No significant dromotropic effects were observed.