Role of daunorubicinol in daunorubicin-induced cardiotoxicity as evaluated with the model of isolated perfused rat heart.

Cardiotoxicity is the major side-effect and limits the clinical use of the anthracyclines, doxorubicin and daunorubicin. A special problem is raised by the metabolites of these drugs, the amount of which may vary according to drug combinations and formulations. Doxorubicinol, the 13-dihydroderivative of doxorubicin, has been shown to be more cardiotoxic than unchanged doxorubicin. Daunorubicinol has been assumed also to be more cardiotoxic than unchanged daunorubicin but its direct effect on cardiac function has never been evaluated in preclinical models. We have compared the cardiac effects (developed pressure, contractility and relaxation of the left ventricle) induced by daunorubicinol to those induced by daunorubicin, using the model of the isolated perfused rat heart. After treatment of rats with 6 doses of 3 mg/kg intraperitoneally, daunorubicin strongly decreased the cardiac functional parameters, while daunorubicinol did not induce cardiotoxicity. Both treatments induced a similar accumulation of daunorubicinol in the myocardium, while daunorubicin was only found in the hearts of rats treated with this drug. Direct perfusion of the hearts of untreated rats with both drugs at 10 microM induced a depression in heart function, but daunorubicin induced a progressive increase in diastolic pressure, reflecting the difficulties encountered by the heart to maintain its activity in the presence of this drug, while daunorubicinol did not. We conclude that daunorubicinol is not responsible for the important cardiac toxicity of daunorubicin.