Metabolism and disposition of a novel b-Cell lymphoma-2 inhibitor venetoclax in humans and characterization of its unusual metabolites

Hong Liu*, Melissa J. Michmerhuizen, Yanbin Lao, Katty Wan, Ahmed Hamed Salem, James Sawicki, Michael Serby, Srirajan Vaidyanathan, Shekman L. Wong, Suresh Agarwal, Martin Dunbar, Jens Sydor, Sonia M. De Morais, Anthony J. Lee

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


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 absorptionwas 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-((4.-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1.-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide] (13%) in feces. Biotransformation of venetoclax in humans primarily involves enzymatic oxidation on the dimethyl cyclohexenylmoiety, 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 a-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.

Original languageEnglish
Pages (from-to)294-305
Number of pages12
JournalDrug Metabolism and Disposition
Issue number3
StatePublished - Mar 2017
Externally publishedYes


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