| Popis: |
Pharmacokinetics on plasma and blood cells concentration, tissue distribution and excretion of amrubicin hydrochloride (SM-5887), a novel antitumor agent, were investigated after a single intravenous administration of 14C-labeled SM-5887 at the doses of 0.1, 1 and 10 mg/kg to rats. 1. The radioactivity levels in plasma and blood cells at these doses decreased multi-exponentially, and the levels of radioactivity in blood cells were 1/2 ?? 1/3 of those present in plasma. The time course profiles were almost parallel among these doses (0.1 ?? 10 mg/kg), and the linear relationship in the area under the concentration time-curve and administered doses was observed. 2. Plasma and blood cell concentrations of the unchanged SM-5887 at these doses decreased more rapidly than those of total radioactivity, and the levels in blood cells were about a half of those in plasma. The α, β and γ-phase half-lives of SM-5887 concentration in plasma were 1.8 min, 29 min and 1.9 hr, respectively. 3. The concentrations of amrubicinol (SM-5887-13-OH), the major bioactive metabolite, in plasma and blood cells increased rapidly, and then decreased slowly. In blood cells, the level of SM-5887-13-OH was three times as high as that in plasma. Other aglycone metabolites without the sugar moiety were also detected in plasma and blood cells. 4. The radioactivity level was relatively high in such tissues as bone marrow, intestinal wall, skin, adrenal, spleen, lung, Harderian gland, submaxillary gland, kidney and liver at 1 ?? 4 hr after administration. Then the radioactivity disappeared gradually from most tissues in a similar profile as that in plasma, except a few tissues such as testis, submaxillary gland, thymus and hair. 5. Within 168 hr after administration, 13% and 76% of the dosed radioactivity was excreted into urine and feces, respectively. Within 72 hr after administration, 58% of the dosed radioactivity was excreted into bile. After intraduodenal injection of the bile to the bile-duct cannulated rats, 31% of the injected radioactivity was reabsorbed. 6. Little difference in pharmacokinetic profile was observed between male and female rats. 7. In vitro protein binding of SM-5887 and SM-5887-13-OH in mammalian plasma and HSA were 92 ?? 97% and 78 ?? 93%, respectively. In vivo plasma protein binding of SM-5887 and SM-5887-13-OH after intravenous administration of SM-5887 to rats were 93 ?? 96% and 82 ?? 89%, respectively. |
