Ibuprofen, pharmacokinetics and pharmacodynamics in the isolated rabbit heart.
Myocardial pharmacokinetics and dynamic effects of the non-steroidal antiinflammatory drug ibuprofen were studied in isolated, spontaneously beating and retrogradely perfused rabbit hearts. Both myocardial uptake and disposition of ibuprofen showed two-compartment characteristics, which possibly reflects extracellular and intracellular binding sites. Initial and terminal kinetic half-lives were about 0.6 and 13.4 min., respectively. Vd beta was about 82 ml/g myocardial tissue. Stepwise increased ibuprofen concentrations from 30 to 160 micrograms/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. Oxygen consumption increased simultaneously to 143% at 160 micrograms/ml and then decreased. Myocardial contractility (measured by amplitude and rate of contraction) decreased progressively to about 55% at concentrations from 60-160 micrograms/ml and further to 20% at 580 micrograms/ml. Myocardial efficiency expressed as the ratio of contraction rate to oxygen consumption decreased to about 0.2. Heart beat frequency decreased simultaneously to 73%. The electrocardiographic 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 micrograms/ml. The findings suggest that ibuprofen at therapeutic concentrations may possibly produce some coronary vasodilation accompanied by a slight negative inotropic effect. Interactions with other cardioactive drugs seem possible. The drug may cause direct cardiotoxic effects at supratherapeutic concentrations.
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D006321:Heart / Q000187:drug effects*; D007052:Ibuprofen / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D011485:Protein Binding; D011817:Rabbits; D014664:Vasodilation / Q000187:drug effects
D007052:Ibuprofen