PT  - JOURNAL ARTICLE
AU  - Hong Liu
AU  - Melissa J. Michmerhuizen
AU  - Yanbin Lao
AU  - Katty Wan
AU  - Ahmed Hamed Salem
AU  - James Sawicki
AU  - Michael Serby
AU  - Srirajan Vaidyanathan
AU  - Shekman L. Wong
AU  - Suresh Agarwal
AU  - Martin Dunbar
AU  - Jens Sydor
AU  - Sonia M. de Morais
AU  - Anthony J. Lee
TI  - Metabolism and Disposition of a Novel B-Cell Lymphoma-2 Inhibitor Venetoclax in Humans and Characterization of Its Unusual Metabolites
AID  - 10.1124/dmd.116.071613
DP  - 2017 Mar 01
TA  - Drug Metabolism and Disposition
PG  - 294--305
VI  - 45
IP  - 3
4099  - http://dmd.aspetjournals.org/content/45/3/294.short
4100  - http://dmd.aspetjournals.org/content/45/3/294.full
SO  - Drug Metab Dispos2017 Mar 01; 45
AB  - Venetoclax (ABT-199), a B-cell lymphoma-2 (Bcl-2) protein inhibitor, is currently in clinical development for the treatment of hematologic malignancies. We characterized the absorption, metabolism, and excretion of venetoclax in humans. After a single oral dose of [14C]venetoclax to healthy volunteers, the recovery of total radioactive dose was 100%, with feces being the major route of elimination of the administered dose, whereas urinary excretion was minimal (<0.1%). The extent of absorption was estimated to be at least 65%. Venetoclax was primarily cleared by hepatic metabolism (∼66% of the administered dose). ∼33% of the administered dose was recovered as the parent drug and its nitro reduction metabolite M30 [2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-amino-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4-(4-((4ʹ-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1ʹ-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide] (13%) in feces. Biotransformation of venetoclax in humans primarily involves enzymatic oxidation on the dimethyl cyclohexenyl moiety, followed by sulfation and/or nitro reduction. Nitro reduction metabolites were likely formed by gut bacteria. Unchanged venetoclax was the major drug-related material in circulation, representing 72.8% of total plasma radioactivity. M27 (oxidation at the 6 position of cyclohexenyl ring followed by cyclization at the α-carbon of piperazine ring; 4-[(10aR,11aS)-7-(4-chlorophenyl)-9,9-dimethyl-1,3,4,6,8,10,10a,11a-octahydropyrazino[2,1-b][1,3]benzoxazin-2-yl]-N-[3-nitro-4-(tetrahydropyran-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide) was identified as a major metabolite, representing 12% of total drug-related material. M27 was primarily formed by cytochrome P450 isoform 3A4 (CYP3A4). Steady-state plasma concentrations of M27 in human and preclinical species used for safety testing suggested that M27 is a disproportionate human metabolite. M27 is not expected to have clinically relevant on- or off-target pharmacologic activities.