Metabolism and disposition of [14C]BMS-690514, an ErbB/vascular endothelial growth factor receptor inhibitor, after oral administration to humans

Drug Metab Dispos. 2010 Nov;38(11):2049-59. doi: 10.1124/dmd.110.034850. Epub 2010 Jul 28.

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), 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 [(14)C]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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Absorption
  • Administration, Oral
  • Adolescent
  • Adult
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / urine
  • Bile / chemistry
  • Biotransformation
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cytochrome P-450 CYP2D6 / genetics
  • Cytochrome P-450 CYP2D6 / metabolism
  • Dose-Response Relationship, Drug
  • Feces / chemistry
  • Glucuronides / metabolism
  • Glucuronosyltransferase / genetics
  • Glucuronosyltransferase / metabolism
  • Humans
  • Hydroxylation
  • Male
  • Oxidation-Reduction
  • Piperidines / blood
  • Piperidines / metabolism
  • Piperidines / pharmacokinetics*
  • Piperidines / pharmacology
  • Piperidines / urine
  • Polymorphism, Single Nucleotide
  • Protein Kinases / metabolism
  • Pyrroles / blood
  • Pyrroles / metabolism
  • Pyrroles / pharmacokinetics*
  • Pyrroles / pharmacology
  • Pyrroles / urine
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Tissue Distribution
  • Triazines / blood
  • Triazines / metabolism
  • Triazines / pharmacokinetics*
  • Triazines / pharmacology
  • Triazines / urine
  • Young Adult

Substances

  • Antineoplastic Agents
  • BMS-690514
  • Glucuronides
  • Piperidines
  • Pyrroles
  • Triazines
  • Cytochrome P-450 CYP2D6
  • UGT1A1 enzyme
  • Glucuronosyltransferase
  • Protein Kinases
  • Receptor Protein-Tyrosine Kinases