title: In vitro characterization of the metabolic pathways and cytochrome P450 inhibition and induction potential of BMS-690514, an ErbB/vascular endothelial growth factor receptor inhibitor.
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) is a potent inhibitor of ErbB human epidermal growth factor receptors (HER1, 2, and 4) and vascular endothelial growth factor receptors 1 to 3 that has been under clinical development for solid tumor malignancies. BMS-690514 is primarily cleared by metabolism with the primary metabolic pathways being direct glucuronidation (M6), hydroxylation (M1, M2, and M37), and O-demethylation (M3). In the current investigation, the metabolic drug-drug interaction potential of BMS-690514 was evaluated in a series of in vitro studies. Reaction phenotyping experiments with cDNA-expressed human cytochrome P450 (P450) and UDP-glucuronosyltransferase (UGT) enzymes and human liver microsomes (HLM) in the presence of P450 or UGT inhibitors suggested that CYP3A4, CYP2D6, and CYP2C9 were the major enzymes responsible for the oxidative metabolism of BMS-690514, whereas both UGT2B4 and UGT2B7 were responsible for the formation of M6. BMS-690514 did not cause direct or time-dependent inhibition of P450 enzymes (IC(50) values ≥40 μM) in incubations with HLM and probe substrates of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4. The compound also did not substantially induce CYP1A1, CYP1A2, CYP2B6, CYP3A4, or UGT1A1 at concentrations up to 10 μM in cultured human hepatocytes. Considering the submicromolar plasma C(max) concentration at the anticipated clinical dose of 200 mg, BMS-690514 is unlikely to cause clinically relevant drug-drug interactions when coadministered with other medications. In addition, because multiple enzymatic clearance pathways are available for the compound, inhibition of an individual metabolic pathway either via coadministered drugs or gene polymorphisms is not expected to cause pronounced (>2-fold) increases in BMS-690514 exposure.
authors.affiliation: Department of Biotransformation, Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research, Route 206 and Province Line Rd., Princeton, NJ 08543, USA.
authors.forename: Haizheng
authors.initials: H
authors.lastname: Hong
authors.forename: Hong
authors.initials: H
authors.lastname: Su
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.forename: Ming
authors.initials: M
authors.lastname: Yao
authors.forename: Ramaswamy A
authors.initials: RA
authors.lastname: Iyer
authors.forename: W Griffith
authors.initials: WG
authors.lastname: Humphreys
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Christopher
mesh_terms: D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014227:Triazines / Q000494:pharmacology*; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism
chemical_list: C552150:BMS-690514; D065607:Cytochrome P-450 Enzyme Inhibitors; D010880:Piperidines; D011758:Pyrroles; D014227:Triazines; D014535:Uridine Diphosphate Glucuronic Acid; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; C486404:UGT2B4 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor