Tumor-selective distribution of an active metabolite of the 9-aminoanthracycline amrubicin

It has been reported that the 9-aminoanthracycline amrubicin shows good eff icacy in human tumor xenograft models, We studied the disposition and metab olism of amrubicin in mice, in comparison with those of doxorubicin. Amrubi cinol, a 13-hydroxy metabolite of amrubicin, which is 10 to 100 times more cytotoxic than amrubicin, was detected as a major metabolite in blood and t issues, and aglycones of amrubicin were also detected. A pharmacokinetic st udy revealed that amrubicin had a smaller distribution volume and a shorter half-life than doxorubicin, In several normal tissues, the levels of amrub icin and amrubicinol were lower than those of doxorubicin. In contrast, the tumor levels of amrubicinol in the mice treated with amrubicin were higher than those of doxorubicin in the mice treated with that drug, in tumors th at are sensitive to amrubicin, These results suggest that the potent therap eutic activity of amrubicin is caused by the selective distribution of its highly active metabolite, amrubicinol, in tumors.