Abstract
(+)-1,4-Dihydro-7-(trans-3-methoxy-4-methylamino-1-pyrrolidinyl)-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid (voreloxin; formerly SNS-595 or AG-7352) is currently under investigation for the treatment of platinum-resistant ovarian cancer and acute myeloid leukemia. In vitro voreloxin undergoes minimal cytochrome P450 (P450) and UDP glucuronosyltransferase (UGT)-mediated metabolism, and in vivo excretion of unchanged voreloxin as the major species is consistent with the slow rate of metabolism observed in vitro. The objective of the present study was to examine the cross-species metabolic profile of voreloxin and to identify and characterize the metabolites formed in rats. We also investigated baculovirus-expressed human P450s and UGTs to determine which isoforms participated in voreloxin metabolism. Incubations using human, monkey, and rat liver microsomes showed monkey and rat metabolism is similar to human. Voreloxin and metabolites collected from plasma, bile, and urine from rats administered radiolabeled voreloxin were separated by high-performance liquid chromatography, and their structures were elucidated by liquid chromatography/tandem mass spectrometry. Activity of metabolites was determined with authentic reference standards in cell-based cytotoxicity assays. The proposed structures of metabolites suggest that metabolic pathways for voreloxin include glucuronide conjugation, oxidation, N-dealkylation, and O-dealkylation.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.023432.
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ABBREVIATIONS: voreloxin, (+)-1,4-dihydro-7-(trans-3-methoxy-4-methylamino-1-pyrrolidinyl)-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid; BDC, bile duct-cannulated; HPLC, high-performance liquid chromatography; P450, cytochrome P450; UGT, UDP glucuronosyltransferase; UDPGA, UDP-glucuronic acid; MS, mass spectrometry; JVC, jugular vein-cannulated; LC/MS/MS, liquid chromatography/tandem mass spectrometry; AUC, area under the curve; DMSO, dimethyl sulfoxide; amu, atomic mass unit.
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↵1 Current affiliation: ChemoCentryx, Inc., Mountain View, California.
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↵2 Current affiliation: Gilead Sciences, Inc., Foster City, California.
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↵3 Current affiliation: Nektar Therapeutics, Inc., San Carlos, California.
- Received July 19, 2008.
- Accepted December 5, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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