Correlation of the in vitro biotransformation of H3B-6527 in dog and human hepatocytes with the in vivo metabolic profile of 14C-H3B-6527 in a dog mass balance study

Xenobiotica. 2020 Apr;50(4):458-467. doi: 10.1080/00498254.2019.1643941. Epub 2019 Aug 2.


1. H3B-6527 is an orally available covalent small molecule inhibitor of FGFR4 undergoing evaluation in adults with hepatocellular carcinoma. Absorption, metabolism, transport and elimination of H3B-6527 were investigated in vitro and in a 14C-H3B-6527 beagle dog mass balance study.2. Following intravenous dosing in dogs, unchanged 14C-H3B-6527 represents only 1.6% of the total dose in excreta. The low amount of radioactivity in the dog urine (4.9% of the administered dose), suggests that renal elimination is a minor pathway of clearance for H3B-6527. A majority of the radioactivity was observed in the feces up to 5 days after dose administration, suggesting that drug-related material was secreted in the bile, and that H3B-6527 clearance was mostly driven by metabolism.3. In vitro, H3B-6527 is a substrate of GSTs, CYP3A and P-glycoprotein.4. The major pathways of metabolism were similar in human and dog hepatocytes, and occurred via glutathione (GSH) conjugations and sequential hydrolysis, N-deethylation and hydroxylation.5. The metabolic profile of H3B-6527 was qualitatively similar in dog hepatocytes and plasma/excreta.

Keywords: FGFR4 inhibitor; H3B-6527; mass balance; metabolism; pharmacokinetics.

MeSH terms

  • Animals
  • Biological Availability
  • Biotransformation
  • Dogs
  • Hepatocytes / metabolism
  • Heterocyclic Compounds, 4 or More Rings / metabolism*
  • Humans
  • Metabolome
  • Tissue Distribution


  • H3B-6527
  • Heterocyclic Compounds, 4 or More Rings