Abstract
Pharmacokinetics in plasma and blood cells concentrations, tissue distribution and excretion of amrubicin hydrochloride (SM-5887), a novel antitumor agent, were investigated during and after repeated intravenous administration of 14C-labeled SM-5887 at a dose of 1 mg/kg/day to rats for 14 days.
1. The radioactivity levels in plasma and blood cells at 24 hr after each dosing during repea ted administration increased with the number of dosing, and the concentrations after the 14th dosing were 6 ?? 8 times higher than those after the first dosing. The AUC0-168h after the 14th dosing was almost 5 times as large as that after the first dosing. These concentrations during repeated administration can be simulated closely from the time-course profile after the first dosing.
2. The concentrations of SM-5887 and its metabolites in plasma and blood cells after the 14th dosing were similar to those after the first dosing.
3. The radioactivity levels in the tissues after the 14th dosing were relatively high in the submaxillary gland, Harderian gland, liver, kidney, adrenal and pituitary. The radioactivity disappeared gradually from most tissues, especially from submaxillary gland, testis and hair.
4. In the tissues, the concentrations of SM-5887 after the 14th dosing were high in submaxillary gland, spleen, lung, thymus and bone marrow. Amrubicinol (SM-5887-13-OH) concentrations were high in sub maxillary gland, thymus and adrenal. Met B concentrations were high in Harderian gland, submaxillary gland, adrenal and kidney. The ratios of the unextracted radioactivity, that was probably attributed mainly to polar metabolites, in plasma, liver, and bladder, were relatively high.
5. The excretion ratios of radioactivity into urine and feces with in 168 hr after 14th dosing, were 14% and 80% of the total dosed radioactivity, respectively. This result was similar to that after a single dosing.
