title: Metabolism and Disposition of Cabozantinib in Healthy Male Volunteers and Pharmacologic Characterization of Its Major Metabolites.
abstract: Metabolism and excretion of cabozantinib, an oral inhibitor of receptor tyrosine kinases, was studied in 8 healthy male volunteers after a single oral dose of 175 mg cabozantinib l-malate containing (14)C-cabozantinib (100 µCi/subject). Total mean radioactivity recovery within 48 days was 81.09%; radioactivity was eliminated in feces (53.79%) and urine (27.29%). Cabozantinib was extensively metabolized with 17 individual metabolites identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in plasma, urine, and feces. Relative plasma radioactivity exposures (analyte AUC0-t/total AUC0-t for cabozantinib+major metabolites) were 27.2, 25.2, 32.3, 7, and 6% for cabozantinib and major metabolites monohydroxy sulfate (EXEL-1646), 6-desmethyl amide cleavage product sulfate (EXEL-1644), N-oxide (EXEL-5162), and amide cleavage product (EXEL-5366), respectively. Comparable relative plasma exposures determined by LC-MS/MS analysis were 32.4, 13.8, 45.9, 4.9, and 3.1%, respectively. These major metabolites each possess in vitro inhibition potencies ≤1/10th of parent cabozantinib against the targeted kinases MET, RET, and VEGFR2/KDR. In an in vitro cytochrome P450 (CYP) panel, cabozantinib and EXEL-1644 both inhibited most potently CYP2C8 (Kiapp = 4.6 and 1.1 µM, respectively). In an in vitro drug transporter panel, cabozantinib inhibited most potently MATE1 and MATE2-K (IC50 = 5.94 and 3.12 µM, respectively) and was a MRP2 substrate; EXEL-1644 inhibited most potently OAT1, OAT3, OATP1B1, MATE1, and OATP1B3 (IC50 = 4.3, 4.3, 6.1, 16.7, and 20.6 µM, respectively) and was a substrate of MRP2, OAT3, OATP1B1, OATP1B3, and possibly P-gp. Therefore, cabozantinib appears to be the primary pharmacologically active circulating analyte, whereas both cabozantinib and EXEL-1644 may represent potential for drug-drug interactions.
authors.affiliation: Department of Non-Clinical Development (S.L., B.H., D.M., L.N.) and Translational Medicine (D.A.), Exelixis, Inc., South San Francisco, California; and QPS, LLC, Newark, Delaware (R.W.) slacy@exelixis.com.
authors.forename: Steven
authors.initials: S
authors.lastname: Lacy
authors.affiliation: Department of Non-Clinical Development (S.L., B.H., D.M., L.N.) and Translational Medicine (D.A.), Exelixis, Inc., South San Francisco, California; and QPS, LLC, Newark, Delaware (R.W.).
authors.forename: Bih
authors.initials: B
authors.lastname: Hsu
authors.affiliation: Department of Non-Clinical Development (S.L., B.H., D.M., L.N.) and Translational Medicine (D.A.), Exelixis, Inc., South San Francisco, California; and QPS, LLC, Newark, Delaware (R.W.).
authors.forename: Dale
authors.initials: D
authors.lastname: Miles
authors.affiliation: Department of Non-Clinical Development (S.L., B.H., D.M., L.N.) and Translational Medicine (D.A.), Exelixis, Inc., South San Francisco, California; and QPS, LLC, Newark, Delaware (R.W.).
authors.forename: Dana
authors.initials: D
authors.lastname: Aftab
authors.affiliation: Department of Non-Clinical Development (S.L., B.H., D.M., L.N.) and Translational Medicine (D.A.), Exelixis, Inc., South San Francisco, California; and QPS, LLC, Newark, Delaware (R.W.).
authors.forename: Ronghua
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Non-Clinical Development (S.L., B.H., D.M., L.N.) and Translational Medicine (D.A.), Exelixis, Inc., South San Francisco, California; and QPS, LLC, Newark, Delaware (R.W.).
authors.forename: Linh
authors.initials: L
authors.lastname: Nguyen
mesh_terms: D000328:Adult; D000813:Anilides / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D019540:Area Under Curve; D001652:Bile Ducts / Q000378:metabolism / Q000502:physiology; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D004912:Erythrocytes / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics* / Q000633:toxicity; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D000813:Anilides; D001798:Blood Proteins; D002352:Carrier Proteins; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C558660:cabozantinib; D003577:Cytochrome P-450 Enzyme System; D011505:Protein-Tyrosine Kinases