TY - JOUR T1 - In Vitro Characterization of the Metabolic Pathways and P450 Inhibition and Induction Potential of BMS-690514, an ErbB/VEGFR Inhibitor JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.111.039776 SP - dmd.111.039776 AU - Haizheng Hong AU - Hong Su AU - Li Ma AU - Ming Yao AU - Ramaswamy A. Iyer AU - William G Humphreys AU - Lisa J. Christopher Y1 - 2011/06/14 UR - http://dmd.aspetjournals.org/content/early/2011/06/14/dmd.111.039776.abstract N2 - BMS-690514 is a potent inhibitor of ErbB human epidermal growth factor receptors (HER1, 2, and 4) and vascular endothelial growth factor receptors (VEGFR1-3) 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, 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 P450 and UGT enzymes and human liver microsomes (HLMs) 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, while both UGT2B4 and UGT2B7 were responsible for the formation of M6. BMS-690514 did not cause direct or time-dependent inhibition of P450 enzymes (IC50 values ≥40 μM) in incubations with HLMs 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 Cmax concentration at the anticipated clinical dose of 200 mg, BMS-690514 is unlikely to cause clinically relevant drug-drug interactions when co-administered with other medications. In addition, since multiple enzymatic clearance pathways are available for the compound, inhibition of an individual metabolic pathway either via co-administered drugs or gene polymorphisms is not expected to cause pronounced (>2-fold) increases in BMS-690514 exposure. ER -