RT Journal Article SR Electronic T1 Metabolism and Disposition of [14C]BMS-690514, an ErbB/Vascular Endothelial Growth Factor Receptor Inhibitor, after Oral Administration to Humans JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 2049 OP 2059 DO 10.1124/dmd.110.034850 VO 38 IS 11 A1 Lisa J. Christopher A1 Haizheng Hong A1 Blisse J. Vakkalagadda A1 Pamela L. Clemens A1 Hong Su A1 Vikram Roongta A1 Alban Allentoff A1 Haojun Sun A1 Kevin Heller A1 Christopher T. Harbison A1 Ramaswamy A. Iyer A1 William G. Humphreys A1 Tai Wong A1 Steven Zhang YR 2010 UL http://dmd.aspetjournals.org/content/38/11/2049.abstract AB (3R,4R)-4-Amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)-3-piperidinol (BMS-690514), an oral selective inhibitor of human epidermal growth factor receptors 1 (or epidermal growth factor receptor), 2, and 4, and vascular endothelial growth factor receptors 1, 2, and 3, is being developed as a treatment for patients with non–small-cell lung cancer and metastatic breast cancer. The disposition of [14C]BMS-690514 was investigated in nine healthy male subjects (group 1, n = 6; group 2, n = 3) after oral administration of a 200-mg dose. Urine, feces, and plasma were collected from all subjects for up to 12 days postdose. In group 2 subjects, bile was collected from 3 to 8 h postdose. Across groups, approximately 50 and 34% of administered radioactivity was recovered in the feces and urine, respectively. An additional 16% was recovered in the bile of group 2 subjects. Less than 28% of the dose was recovered as parent drug in the combined excreta, suggesting that BMS-690514 was highly metabolized. BMS-690514 was rapidly absorbed (median time of maximum observed concentration 0.5 h) with the absorbed fraction estimated to be approximately 50 to 68%. BMS-690514 represented ≤7.9% of the area under the concentration-time curve from time 0 extrapolated to infinite time of plasma radioactivity, indicating that the majority of the circulating radioactivity was from metabolites. BMS-690514 was metabolized via multiple oxidation reactions and direct glucuronidation. Circulating metabolites included a hydroxylated rearrangement product (M1), a direct ether glucuronide (M6), and multiple secondary glucuronide conjugates. None of these metabolites is expected to contribute to the pharmacology of BMS-690514. In summary, BMS-690514 was well absorbed and extensively metabolized via multiple metabolic pathways in humans, with excretion of drug-related radioactivity in both bile and urine.