Abstract

Daunomycin, a glycosidic anthracycline, is metabolized in vitro to two newly identified aglycone metabolites, 8-(1-hydroxyethyl)-7,8,9,10-tetrahydro-6,8,11-trihydroxyl-1-methoxy-5, 12-naphthacenedione (D_z) and 8-acetyl-7,8,9,10-tetrahydro-6,8,11-trihydroxyl-1-methoxy-5, 12-naphthacenedione (D_y). Two similar aglycone metabolites of adriamycin have been identified as 8-(1,2-dihydroxyethyl)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5, 12-naphthacenedione (A_z), and 8-hydroxyacetyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5, 12-naphthacenedione (A_y). At least two distinct reactions are involved in the formation of these metabolites. One is a reductive glycosidic cleavage which occurs in the conversion of daunomycin to D_y and in the conversion of the glycosidic metabolite D₂ to D_z. The other reaction is dependent upon the reduction of the acetyl group of daunomycin to hydroxy ethyl. This occurs in the conversions of daunomycin to D₂ and of D_y to D_z. The adriamycin reactions are analogous to those of daunomycin. Daunomycin is metabolized by liver and kidney homogenates. In liver the metabolic pathway proceeds by conversion of daunomycin (D₁) to D_y, which is then converted to D_x. In kidney, the sequence involves conversion of D₁ to a glycosidic metabolite D₂ which is then converted to D_x. Thus, the major difference between the liver and kidney pathways seems to be the order in which the two reactions occur. In the postulated pathway for adriamycin metabolism in hamster and rat liver, adriamycin is converted to A_y which is, in turn, converted to A_x.