Metabolism and Disposition of [14C]BMS-690514 after Oral Administration to Rats, Rabbits, and Dogs

Abstract

(3R,4R)-4-Amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f] [1,2,4]triazin-5-yl)methyl)-3-piperidinol (BMS-690514) is a potent inhibitor of human epidermal growth factor receptors 1, 2, and 4 and vascular endothelial growth factor receptors 1 through 3. BMS-690514 is an oral oncologic agent currently being developed for the treatment of patients with advanced non-small cell lung cancer and breast cancer. In this investigation, a series of studies was conducted to determine the biotransformation of [(14)C]BMS-690514 after oral administration to rats, rabbits, and dogs. After administration of a single oral dose of [(14)C]BMS-690514 to rats and dogs, the majority of the radioactive dose (61-71%) was recovered in the feces, whereas 18 to 20% was eliminated in urine. In bile duct-cannulated rats, 83 and 17% of the administered radioactivity was recovered in the bile and urine, respectively, suggesting that biliary secretion was a major route for the elimination of BMS-690514-derived radioactivity in rats. The parent compound underwent extensive metabolism in both species, with <12% of the administered radioactivity recovered as BMS-690514 in the excreta samples. Metabolite profiles in plasma were qualitatively similar in rats, rabbits, and dogs. Unchanged BMS-690514 was a prominent drug-related component in the plasma profiles from all the species. However, multiple metabolites contributed significantly to the circulating radioactivity, particularly for rabbit and dog, in which metabolites comprised 73 to 93% of the area under the time curve (0-8 h). Circulating metabolites included M6, a direct O-glucuronide conjugate; M1, a hydroxylated metabolite; and glucuronide conjugates of hydroxylated and O-demethylated metabolites. Overall, the results from these studies suggested that BMS-690514 was well absorbed and highly metabolized through multiple pathways in these preclinical species.