Absorption, distribution, metabolism, and excretion of mTOR kinase inhibitor CC-223 in rats, dogs, and humans

摘要

1.The absorption, distribution, metabolism, and excretion of CC-223 were studied following a single oral dose of [C-14]CC-223 to rats (3 mg/kg; 90 mu Ci/kg), dogs (1.5 mg/kg; 10 mu Ci/kg), and healthy volunteers (20 mg; 200 nCi). 2.CC-223-derived radioactivity was widely distributed in rats. Excretion of radioactivity was rapid and nearly complete from rats (87%), dogs (78%), and humans (97%). Feces was the major excretion pathway for rats (67%) and dogs (70%), whereas urine (57.6%) was the major elimination route for humans. Urine and bile each contained approximately 20% administered radioactivity in rats, whereas bile (20%) played a more important role than urine (10%) in the excretion of absorbed radioactivity in dogs. Based on excretion data, CC-223 had good absorption, with greater than 56%, 29%, and 57% of the oral dose absorbed in rats, dogs, and humans, respectively. 3.CC-223 was the prominent radioactive component in circulation of rats (71% of the exposure to total radioactivity) and dogs (= 45.5%), whereas M1 (76.5%) was the predominant circulating metabolite in humans. M1 and M1-derived metabolites accounted for 66% of human dose. CC-223 was extensively metabolized in rats, dogs, and humans through glucuronidation, O-demethylation, oxidation, and combinations of these pathways.