Daunorubicin and its hydroxy metabolite in cardiomyocytes: insights into cellular kinetics, toxicity, DNA damage, and dexrazoxane-induced cardioprotection

Anthracycline anticancer agents, such as daunorubicin and doxorubicin, rank among the most effective and widely used anticancer drugs. However, their benefit is markedly reduced by the risk of severe cardiotoxicity. Anthracyclines undergo metabolic reduction of the side chain carbonyl group, producing hydroxy metabolites implicated in the cardiotoxicity. This study investigated toxicity, metabolism and cellular disposition of daunorubicin and its hydroxy metabolite, daunorubicinol, in isolated rat neonatal cardiomyocytes. Daunorubicin induced concentration-dependent cytotoxicity, whereas the toxicity of exogenously administered daunorubicinol was significantly lower despite induction of similar DNA damage. UHPLC-MS analyses revealed that daunorubicin rapidly penetrates cardiomyocytes and is metabolized to daunorubicinol, which is then released from the cells. The intracellular concentration of daunorubicinol was consistently lower than that of daunorubicin, indicating a reduced tendency for daunorubicinol to accumulate in cardiomyocytes. P-glycoprotein 1 has been shown to actively facilitate the efflux of both daunorubicin and daunorubicinol from cardiomyocytes. Dexrazoxane, the only approved agent for anthracycline cardiotoxicity prevention, did not affect the cellular metabolism or disposition of daunorubicin or its hydroxy metabolite, but it effectively reduced not only daunorubicin-induced cardiotoxicity, but also provided protection against the lower toxicity of daunorubicinol. Moreover, dexrazoxane reduced DNA damage induced by both daunorubicin and its hydroxy metabolite. These findings suggest that daunorubicin is the primary driver of cardiomyocyte cytotoxicity, while its hydroxy metabolite, daunorubicinol, plays a more limited role, challenging the notion that it serves as a significant toxic reservoir.