The disposition of 4'-epi-[14-14C]doxorubicinHCl (4'-epi-[14C]DXR) and [14-14C]doxorubicinHCl [( 14C]DXR) was studied in male Sprague-Dawley rats given 1 mg/kg body weight IV. Most of the radioactivity administered was recovered in the faeces (two-thirds of the dose within 6 days after administration), urine accounting for 15% of the 14C given during the same period. A significant amount of radioactivity was also found in expired air. Significantly higher levels of radioactivity were recorded in the plasma (40 min and 4 h) and liver (40 min) in [14C]DXR-treated animals, whereas in animals treated with 4'-epi-[14C]DXR a higher specific radioactivity was found in the kidneys (40 min and 4 h) and bone marrow (40 min). The total tissue residual radioactivity was greater (P less than 0.05) at 24 h for [14C]DXR (45.8%) than for 4'-epi-[14C]DXR (38.6%). The main radioactive species in urines were the unchanged drugs. Minor metabolites were represented by a polar fraction, 13-dihydroderivatives, and aglycones. Whereas aglycones represent an important fraction of extractable tissue radioactivity in liver samples of many of the treated animals, the unchanged drug was invariably the major radioactive component in spleen, lung, and kidney. Liver extraction studies showed the presence of significant amounts of bound radioactivity that could be recovered in soluble form only after incubation with deoxyribonuclease. The main radioactive species present in the bile were the unchanged drug and a polar fraction. The amount of the former was higher in [14C]DXR-treated than in 4'-epi-[14C]DXR-treated animals. On the other hand, partial glucuronidation of 4'-epi-[14C]DXR was deduced on the basis of results of enzymic hydrolysis of bile samples.

The disposition of [14-14C]4-demethoxydaunorubicin HCl ([14-14C]idarubicin HCl, [14C]IDR) and of [14-14C]daunorubicin HCl ([14C]DNR) was studied in male Sprague Dawley rats. [14C]IDR was administered either IV at 0.25 mg/kg body weight or PO at 1 mg/kg body weight, whereas [14C]DNR was dosed IV at 1 mg/kg body weight. The main elimination route for both compounds was the bile, fecal excretion representing 0.75-0.8 times the total dose at 72 h. Radioactivity due to [14C]IDR-derived species is released by the tissues at a slower rate than activity derived from [14C]DNR. After IV treatment comparable plasma levels are obtained, but tissue radioactivity is markedly lower with [14C]IDR, in keeping with the lower dosage. The ratio of plasma to tissue radioactivity is even higher in animals treated PO with [14C]IDR, because of the more extensive metabolism after this route of administration. The 13-dihydro derivatives of both [14C]IDR and [14C]DNR are the main metabolites in tissues, but in the case of the former, products of phase II reactions become more important at later times in liver and kidney and in excreta.