Ibuprofen, Pharmacokinetics and Pharmacodynamics in the Isolated Rabbit Heart

Abstract

Myocardial pharmacokinetics and dynamic effects of the nonsteroidal antiinflammatory drug ibuprofen were studied in isolated, spontaneously beating and retrogradely perfused rabbit hearts. Both myocardial uptake and disposition of ibuprofen showed 2-compartment characteristics, which possibly reflects extracellular and intracellular binding sites. Initial and terminal kinetic half-lives were .apprx. 0.6 and 13.4 min, respectively. Vd.beta. was .apprx. 82 ml/g myocardial tissue. Stepwise increased ibuprofen concentrations from 30 to 160 .mu.g/ml in the Krebs-Henseleit perfusion liquid produced a progressive increase in coronary flowrate up to 178%, which then decreased somewhat at higher concentrations. Preliminary observations showed a direct relaxing effect on PGF-2.alpha. produced contractions in coronary vasculature. O2 consumption increased simultaneously to 143% at 160 .mu.g/ml and then decreased. Myocardial contractility (measured by amplitude and rate of contraction) decreased progressively to .apprx. 55% at concentrations from 60-160 .mu.g/ml and further to 20% at 580 .mu.g/ml. Myocardial efficiency expressed as the ratio of contraction rate to O2 consumption decreased to .apprx. 0.2. Heart beat frequency decreased simultaneously to 73%. The ECG PQ and QRS intervals increased to 143 and 139%, respectively, whereas the QT interval did not increase significantly. Asystolia occurred in some cases at ibuprofen concentrations of 580 .mu.g/ml. Ibuprofen at therapeutic concentrations may possibly produce some coronary vasodilation by a slight negative inotropic effect. Interactions with other cardioactive drugs seem possible. The drug may cause direct cardiotoxic effects at supratherapeutic concentrations.