Axitinib is an oral inhibitor of vascular endothelial growth factor receptors 1-3 approved for the treatment of advanced renal cell cancer (RCC). Human [14C]-labelled clinical studies indicate axitinib's primarily route of clearance is metabolism.
The aims of these in vitro experiments were to identify and characterize the enzymes involved in axitinib metabolic clearance. In vitro biotransformation studies of axitinib identified a number of metabolites including an axitinib sulfoxide, several less abundant oxidative metabolites and glucuronide conjugates. The most abundant NADPH- and UDPGA-dependent metabolites, axitinib sulfoxide (M12) and axitinib N-glucuronide (M7) were selected for phenotyping and kinetic study. Phenotyping experiments with human liver microsomes using chemical inhibitors and recombinant human P450s demonstrated axitinib was predominately metabolized by CYP3A4/5, with minor contributions from CYP2C19 and CYP1A2. The Km and Vmax values for the formation of axitinib sulfoxide by CYP3A4 or CYP3A5 were 4. 0 or 1. 9 μM and 9. 6 or 1. 4 pmol·min-1·pmol-1, respectively. Using a CYP3A4 specific inhibitor (Cyp3cide) in liver microsomes expressing CYP3A5, 66% of the axitinib intrinsic clearance was attributable to CYP3A4 and 15% to CYP3A5. Axitinib N-glucuronidation was primarily catalyzed by UGT1A1, verified by chemical inhibitors and UGT1A1 null expressers, with lesser contributions from UGTs 1A3, 1A9, and 1A4. The Km and Vmax describing the formation of the N-glucuronide in HLM or rUGT1A1, were 2. 7 μM or 0. 75 μM and 8. 9 or 8. 3 pmol·min-1·mg-1, respectively. In summary, CYP3A4 is the major enzyme involved in axitinib clearance with lesser contributions from CYP3A5, CYP2C19, CYP1A2, and UGT1A1.
Drug metabolism and disposition: the biological fate of chemicals. 2015 Oct 28 [Epub ahead of print]
Michael A Zientek, Theunis C Goosen, Elaine Tseng, Jonathan N Bauman, Ying Jiang, Sascha Freiwald, Ping Kang, Jian Lin, Gregory S Walker, David Neul, Bill J Smith
Pfizer; Pfizer, Inc;, Pfizer, Inc;, Pfizer Inc;, Self employed;, NSF;, Vertex;, Pfizer Inc;, Pfizer Inc;, Dart Neuroscience;, Gilead.