Comparative cardiotoxicity of idarubicin and doxorubicin using the isolated perfused rat heart model

Attempts to reduce the incidence of congestive heart failure following anthracycline therapy include the replacement of the parent compounds (especially doxorubicin) by less cardiotoxic analogs. Among these analogs, idarubicin (4-demethoxy-daunorubicin) was shown to be less cardiotoxic than doxorubicin in phase II clinical trials, but its actual cardiotoxicity has never been evaluated in large series and has never been compared to that of doxorubicin in relevant experimental models. Using the isolated perfused rat heart model, we compared the cardiac effects (developed pressure, contractility and relaxation of the left ventricle) induced by idarubicin to those induced by doxorubicin. Drugs were administered i.v. every other day for 11 days at doses of 1, 2, 2.5 and 3 mg/kg per injection for doxorubicin and 0.5, 0.75 and 1 mg/kg per injection for idarubicin. We confirmed that similar general toxicity symptoms were obtained for a dose ratio of 1:4 (idarubicin:doxorubicin). However, at the maximum tolerated doses of both drugs (3 mg/kg per injection for doxorubicin and 0.75 mg/kg per injection for idarubicin), the cardiac toxicity of idarubicin remained significantly lower than that of doxorubicin. Anthracycline cardiac accumulation was evaluated in parallel and revealed a lower cardiac accumulation of idarubicin, which could explain the reduced cardiac toxicity of this analog. Direct perfusion of the drugs in the isolated hearts of untreated animals revealed that idarubicin was taken up more readily than doxorubicin in the cardiac tissue, despite the fact that it had less deleterious effects on cardiac function. This indicates that idarubicin also had less intrinsic cardiotoxicity than doxorubicin in this model.