Evaluation of anthracycline cardiotoxicity with the model of isolated, perfused rat heart: comparison of new analogues versus doxorubicin

Abstract

We have compared the cardiotoxicity of 3 anthracyclines in a model of isolated perfused rat heart using the Langendorff technique. The contractile state and ventricular compliance were studied. Doxorubicin, epirubicin and pirarubicin were perfused at concentrations of 10(-6) and 10(-5) M during 70 min. The cardiac accumulation of the drugs was studied by HPLC. No significant alteration of cardiac functional parameters was observed at 10(-6) M. At 10(-5) M, epirubicin produced a significantly greater alteration of cardiac contractility than doxorubicin, whereas pirarubicin exerted first an inotropic effect followed by a recovery to initial values at the 60th min. Anthracycline accumulation in the heart was dose-dependent; epirubicin accumulated to a 30% greater extent than doxorubicin and pirarubicin heart concentrations were 4-5 times higher than those of doxorubicin at the end of the perfusion. These results suggest that doxorubicin and epirubicin have the same intrinsic cardiac toxicity, and that their distinct clinical cardiotoxicity must be explained by pharmacokinetic differences, whereas pirarubicin is much less cardiotoxic than the other anthracyclines because of different pharmacodynamic properties.

Development of the model of rat isolated perfused heart for the evaluation of anthracycline cardiotoxicity and its circumvention

“…This difference is higher than the difference observed by van der Vijgh et al (1990) comparing the AUCs (0-48 h) of doxorubicin and epirubicin in mice hearts. Pirarubicin appeared much less cardiotoxic than doxorubicin both in treated and intact animals; its accumulation after direct heart perfusion was much higher than that of doxorubicin (Pouna et al, 1995) and we therefore attributed its reduced cardiac toxicity to pharmacodynamic reasons related to differences in the mechanism of action of this compound as compared to doxorubicin. However, we now show that, in the intact animal, repeated treatment leads to barely detectable levels of drug accumulation in the heart, which could also well explain its reduced cardiac toxicity.…”

“…The measure of left ventricular ejection fraction is a clinical evaluation of myocardial contractility and is routinely used to monitor anthracycline therapy in human subjects (Basser & Green, 1993), whereas endomyocardial biopsy remains far from routine clinical use. Numerous models have been developed for the understanding of anthracycline cardiotoxicity, using myocardial cells (Jiang et al, 1994), papillary muscles (Lee et al, 1991), microsomes (Vile & Winterbourn, 1989;Ondrias et al, 1990), mitochondria (Solem & Wallace, 1993), isolated atria (Monti et al, 1986;Temma et al, 1993) or isolated hearts directly perfused with anthracyclines (Pelikan et al, 1986;Rabkin, 1983;Del Tacca et al, 1987;Pouna et al, 1995). The interest of these models is to identify the possible targets of anthracyclines in the heart and to understand the Rats were treated with different anthracyclines at equimolar doses, every other day for 11 days.…”

“…Cardiac functional parameters Direct perfusion of doxorubicin, epirubicin and pirarubicin has already been studied and published (Pouna et al, 1995). We wished to evaluate left ventricular dysfunction with this approach and we attempted to correlate it to drug accumulation.…”

“…Discrepancies were also found for daunorubicin, which was shown either less cardiotoxic (De Jong et al, 1993) or more cardiotoxic (Vile & Winterbourn, 1989) than doxorubicin. In previous work, we had studied direct perfusion of several anthracyclines in the isolated heart preparation from untreated rats (Pouna et al, 1995). This approach provided information on the possible mechanisms of cardiac toxicity, but could not take into account drug distribution and metabolism in the intact animal, which appear as a determinant factor of cardiac toxicity.…”

“…Preclinical information on the potential cardiac toxicity of a new drug or of a new association is therefore required before the start of clinical trials. This is why we developed in a first attempt the model of the rat isolated heart, which was perfused with various concentrations of several anthracyclines, as a potential model of cardiac toxicity (Pouna et al, 1995). However, despite the fact that we obtained reproducible alterations of cardiac function, which were different for the anthracyclines tested, this model could not be proposed as such because it bypasses the pharmacokinetic and metabolic steps of the drug in the body, and gave only insights on the direct action of anthracyclines on the heart muscle.…”