Comparative metabolism of daunorubicin and 4-demethoxydaunorubicin in mice and rabbits

In the present study, the biodisposition of 4-demethoxydaunorubicin (4DDM) and its 13-dihydrometabolite was compared with daunorubicin (DM) and its metabolite in rabbit serum, and the results were considered in the light of this DM analog's pharmacokinetic behavior in mice. In rabbit serum, the levels of 13-OH derivative of both DM and 4DDM (daunorubicinol and 4-demethoxydaunorubicinol) were higher than in mice. In vitro metabolic studies with mouse and rabbit cytosol indicated that the hepatic metabolism was quantitatively important for both analogs (70%-90% for DM and 4DDM was reduced to the 13-OH metabolite), but the rabbit had a much higher specific capacity to metabolize these compounds. DM seemed a better substrate for cytoplasmic aldoketoreductase, the enzyme affinity in rabbits being three times higher than for 4DDM. Cytotoxicity studies in vitro showed that 4-demethoxydaunorubicinol, unlike daunorubicinol, was as cytotoxic as the parent compound, and this suggests this metabolic step does not inactivate 4DDM but contributes to its high and long-lasting biological activity in vivo.