Preclinical evaluation of the cardiotoxicity of taxane-anthracycline combinations using the model of isolated perfused rat heart

Paclitaxel strongly potentiates the cardiotoxicity of doxorubicin in the cl inical setting. In this study, we aimed (1) to determine whether this poten tiation could be reproduced in an ex vivo model and, if so, (2) to select d rugs and protocols that did not cause this potentiation. The effect of pacl itaxel and docetaxel on the cardiotoxicity induced by doxorubicin and epiru bicin was studied using the model of isolated perfused rat heart. Cardiac p erformances were evaluated after several combination protocols administered every 2 days over a period of 12 days, and anthracycline concentrations in the heart and liver were determined on Day 12. When administered simultane ously, paclitaxel strongly potentiated the cardiotoxicity of doxorubicin ex vivo, and this effect was not due to Cremophor EL, the solvent used in the formulation of paclitaxel. The potentiation of anthracycline cardiotoxicit y could be avoided by the replacement of doxorubicin by epirubicin, and/or of paclitaxel by docetaxel. Cardiotoxic potentiation was also avoided by th e introduction of a 24-h lag time between the repetitive injections of doxo rubicin and docetaxel, The concentration of doxorubicin and its cardiotoxic metabolite, doxorubicinol, in the heart and liver was not significantly al tered by the taxanes, but that of epirubicin was increased twofold both in the heart and the liver. These results show that the potentiation of doxoru bicin-induced cardiotoxicity by paclitaxel can be reproduced with an ex viv o model, and that it is not related to an increase in tissue concentration of the drug or active metabolite. Our model, therefore, may be useful for t he selection of anthracycline-containing protocols with no increased risk o f cardiotoxicity for the patients. (C) 2000 Academic Press.