title: Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients.
abstract: OBJECTIVE
  Famitinib is a novel multi-targeted receptor tyrosine kinase inhibitor under development for cancer treatment. This study aims to characterize the metabolic and bioactivation pathways of famitinib.
  
  
  METHODS
  The metabolites in human plasma, urine and feces were identified via ultra-high performance liquid chromatography-quadrupole-time of flight-mass spectrometry and confirmed using synthetic standards. Biotransformation and bioactivation mechanisms were investigated using microsomes, recombinant metabolic enzymes and hepatocytes.
  
  
  RESULTS
  Famitinib was extensively metabolized after repeated oral administrations. Unchanged famitinib was the major circulating material, followed by N-desethylfaminitib (M3), whose steady-state exposure represented 7.2 to 7.5% that of the parent drug. Metabolites in the excreta were mainly from oxidative deamination (M1), N-desethylation (M3), oxidative defluorination (M7), indolylidene hydroxylation (M9-1 and M9-5) and secondary phase-II conjugations. CYP3A4/5 was the major contributor to M3 formation, CYP3A4/5 and aldehyde dehydrogenase to M1 formation and CYP1A1/2 to M7, M9-1 and M9-5 formations. Minor cysteine conjugates were observed in the plasma, urine and feces, implying the formation of reactive intermediate(s). In vitro microsomal studies proved that famitinib was bioactivated through epoxidation at indolylidene by CYP1A1/2 and spontaneously defluorinated rearrangement to afford a quinone-imine species. A correlation between famitinib hepatotoxicity and its bioactivation was observed in the primary human hepatocytes.
  
  
  CONCLUSIONS
  Famitinib is well absorbed and extensively metabolized in cancer patients. Multiple enzymes, mainly CYP3A4/5 and CYP1A1/2, are involved in famitinib metabolic clearance. The quinone-imine intermediate formed through bioactivation may be associated with famitinib hepatotoxicity. Co-administered CYP1A1/2 inducers or inhibitors may potentiate or suppress its hepatotoxicity.
authors.affiliation: Centre for Drug Metabolism and Pharmacokinetics Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Cen
authors.initials: C
authors.lastname: Xie
authors.forename: Jialan
authors.initials: J
authors.lastname: Zhou
authors.forename: Zitao
authors.initials: Z
authors.lastname: Guo
authors.forename: Xingxing
authors.initials: X
authors.lastname: Diao
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Gao
authors.forename: Dafang
authors.initials: D
authors.lastname: Zhong
authors.forename: Haoyuan
authors.initials: H
authors.lastname: Jiang
authors.forename: Lijia
authors.initials: L
authors.lastname: Zhang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chen
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000378:metabolism / Q000493:pharmacokinetics*; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism*; D010084:Oxidation-Reduction; D011758:Pyrroles / Q000378:metabolism / Q000493:pharmacokinetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D007527:Isoenzymes; D011758:Pyrroles; C584390:famitinib; D003577:Cytochrome P-450 Enzyme System; D020794:Receptor Protein-Tyrosine Kinases