title: Pharmacokinetics, metabolism, and excretion of [14C]axitinib, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in humans.
abstract: The disposition of a single oral dose of 5 mg (100 μCi) of [(14)C]axitinib was investigated in fasted healthy human subjects (N = 8). Axitinib was rapidly absorbed, with a median plasma Tmax of 2.2 hours and a geometric mean Cmax and half-life of 29.2 ng/ml and 10.6 hours, respectively. The plasma total radioactivity-time profile was similar to that of axitinib but the AUC was greater, suggesting the presence of metabolites. The major metabolites in human plasma (0-12 hours), identified as axitinib N-glucuronide (M7) and axitinib sulfoxide (M12), were pharmacologically inactive, and with axitinib comprised 50.4%, 16.2%, and 22.5% of the radioactivity, respectively. In excreta, the majority of radioactivity was recovered in most subjects by 48 hours postdose. The median radioactivity excreted in urine, feces, and total recovery was 22.7%, 37.0%, and 59.7%, respectively. The recovery from feces was variable across subjects (range, 2.5%-60.2%). The metabolites identified in urine were M5 (carboxylic acid), M12 (sulfoxide), M7 (N-glucuronide), M9 (sulfoxide/N-oxide), and M8a (methylhydroxy glucuronide), accounting for 5.7%, 3.5%, 2.6%, 1.7%, and 1.3% of the dose, respectively. The drug-related products identified in feces were unchanged axitinib, M14/15 (mono-oxidation/sulfone), M12a (epoxide), and an unidentified metabolite, comprising 12%, 5.7%, 5.1%, and 5.0% of the dose, respectively. The proposed mechanism to form M5 involved a carbon-carbon bond cleavage via M12a, followed by rearrangement to a ketone intermediate and subsequent Baeyer-Villiger rearrangement, possibly through a peroxide intermediate. In summary, the study characterized axitinib metabolites in circulation and primary elimination pathways of the drug, which were mainly oxidative in nature.
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism (B.J.S., H.-Z.B., P.K., W.F.P., E.Y.W., D.K.D.), Pfizer Oncology-Clinical Pharmacology (Y.P., B.H., K.J.K.), and Pharmaceutical Sciences (A.J.D.), Pfizer Inc., Worldwide Research and Development, La Jolla Laboratories, San Diego, CA.
authors.forename: Bill J
authors.initials: BJ
authors.lastname: Smith
authors.forename: Yazdi
authors.initials: Y
authors.lastname: Pithavala
authors.forename: Hai-Zhi
authors.initials: HZ
authors.lastname: Bu
authors.forename: Ping
authors.initials: P
authors.lastname: Kang
authors.forename: Brian
authors.initials: B
authors.lastname: Hee
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Deese
authors.forename: William F
authors.initials: WF
authors.lastname: Pool
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Klamerus
authors.forename: Ellen Y
authors.initials: EY
authors.lastname: Wu
authors.forename: Deepak K
authors.initials: DK
authors.lastname: Dalvie
mesh_terms: D000328:Adult; D000077784:Axitinib; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000737:chemistry; D006801:Humans; D007093:Imidazoles / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D007191:Indazoles / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*
chemical_list: D002250:Carbon Radioisotopes; D007093:Imidazoles; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D000077784:Axitinib; D011505:Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor