In Vitro Kinetic Characterization of Axitinib Metabolism S
Supplemental material to this article can be found at: http://dmd.aspetjournals.org/content/suppl/2015/10/28/dmd.115.065615.DC1 1521-009X/44/1/102–114$25.00 http://dx.doi.org/10.1124/dmd.115.065615 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 44:102–114, January 2016 Copyright ª 2015 by The American Society for Pharmacology and Experimental Therapeutics In Vitro Kinetic Characterization of Axitinib Metabolism s Michael A. Zientek, Theunis C. Goosen, Elaine Tseng, Jian Lin, Jonathan N. Bauman, Gregory S. Walker, Ping Kang, Ying Jiang, Sascha Freiwald, David Neul, and Bill J. Smith Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer Inc., San Diego, California (M.A.Z, P.K., Y.J, S.F., D.N, B.J.S.); and Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer Inc., Groton, Connecticut (T.C.G., E.T., J.L., J.N.B, G.S.W.) Received May 26, 2015; accepted October 27, 2015 ABSTRACT N-Methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]- predominately metabolized by CYP3A4/5, with minor contributions benzamide (axitinib) is an oral inhibitor of vascular endothelial from CYP2C19 and CYP1A2. The apparent substrate concentration at growth factor receptors 1–3, which is approved for the treatment half-maximal velocity (Km)andVmax values for the formation of axitinib Downloaded from of advanced renal cell cancer. Human [14C]-labeled clinical studies sulfoxide by CYP3A4 or CYP3A5 were 4.0 or 1.9 mMand9.6or indicate axitinib’s primary route of clearance is metabolism. The 1.4 pmol·min21·pmol21, respectively. Using a CYP3A4-specific inhibitor aims of the in vitro experiments presented herein were to identify (Cyp3cide) in liver microsomes expressing CYP3A5, 66% of the and characterize the enzymes involved in axitinib metabolic clear- axitinib intrinsic clearance was attributable to CYP3A4 and 15% to ance.
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