In Vitro Kinetic Characterization of Axitinib Metabolism

• DOI: 10.1124/dmd.115.065615
• Publication Date: 2015-10-29T02:20:48Z
• Authors: Michael A Zientek; Theunis C Goosen; Elaine Tseng; Jian Lin; Jonathan N Bauman; Gregory S Walker; Ping Kang; Ying Jiang; Sascha Freiwald; David Neul; Bill J Smith
• Keywords: Axitinib; Glucuronide

N-Methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide (axitinib) is an oral inhibitor of vascular endothelial growth factor receptors 1-3, which approved for the treatment advanced renal cell cancer. Human [(14)C]-labeled clinical studies indicate axitinib's primary route clearance metabolism. The aims in vitro experiments presented herein were to identify and characterize enzymes involved axitinib metabolic clearance. In biotransformation identified a number metabolites including sulfoxide, several less abundant oxidative metabolites, glucuronide conjugates. most NADPH- UDPGA-dependent sulfoxide (M12) N-glucuronide (M7) selected phenotyping kinetic study. Phenotyping with human liver microsomes (HLMs) using chemical inhibitors recombinant cytochrome P450s demonstrated was predominately metabolized by CYP3A4/5, minor contributions from CYP2C19 CYP1A2. apparent substrate concentration at half-maximal velocity (Km) Vmax values formation CYP3A4 or CYP3A5 4.0 1.9 µM 9.6 1.4 pmol·min(-1)·pmol(-1), respectively. Using CYP3A4-specific (Cyp3cide) expressing CYP3A5, 66% intrinsic attributable 15% CYP3A5. Axitinib N-glucuronidation primarily catalyzed UDP-glucuronosyltransferase (UGT) UGT1A1, verified UGT1A1 null expressers, lesser UGTs 1A3, 1A9, 1A4. Km describing HLM rUGT1A1 2.7 0.75 8.9 8.3 pmol·min(-1)·mg(-1), summary, major enzyme CYP2C19, CYP1A2, UGT1A1.