Metabolite elucidation of the Hsp90 inhibitor SNX-2112 using ultraperformance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS).

Abstract

1. The novel heat-shock protein 90 inhibitor SNX-2112 is a promising drug candidate for treating various types of cancers. Here we aim to determine the metabolic pathways of SNX-2112 in rats in vivo and in humans in vitro. 2. Metabolite identification was performed using ultraperformance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) method. In vitro metabolism studies were performed using liver and intestine microsomes, as well as recombinant human cytochrome P450 (CYP) enzymes. 3. Analysis of rat plasma, urine, and feces revealed a total of eight metabolites, one reductive metabolite (M1), one structurally unknown metabolite (M2), and six mono-oxidative metabolites (M3-1, M3-2, M3-3, M3-4, M3-5, and M3-6). The reduction, M2, and mono-oxidation pathways were responsible for 0.8 ± 0.3 %, 18.3 ± 9.1 %, and 39.4% ± 6.1 of SNX-2112 clearance from rats, respectively. 4. SNX-2112 was subjected to the same types of metabolism in human liver and intestine microsomes. Reaction phenotyping showed that CYP3A4, 3A5, 2D6, and 1A1 were mainly responsible for SNX-2112 metabolism. 5.  In conclusion, we have elucidated the metabolic pathways of SNX-2112 and highlighted that metabolism was the predominant pathway for its clearance. Better understanding of SNX-2112 metabolism should facilitate the drug development of this promising anti-cancer agent.

• Authors: Wei Liu, Hongming Liu, Hua Sun, Dong Dong, Zhiguo Ma, Yifei Wang, Baojian Wu
• Journal: Xenobiotica; the fate of foreign compounds in biological systems (Xenobiotica) Vol. 44 Issue 5 Pg. 455-64 (May 2014) ISSN: 1366-5928 [Electronic] England
• PMID: 24191862 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Heterocyclic Compounds, 4 or More Rings
• SNX 2112
• Cytochrome P-450 Enzyme System
• CYP1A1 protein, human
• CYP2F1 protein, human
• Cytochrome P-450 CYP1A1
• Cytochrome P-450 CYP2D6
• Cytochrome P450 Family 2

Topics

• Animals
• Chromatography, Liquid (methods)
• Cytochrome P-450 CYP1A1 (metabolism)
• Cytochrome P-450 CYP2D6 (metabolism)
• Cytochrome P-450 Enzyme System (chemistry, metabolism)
• Cytochrome P450 Family 2
• Feces
• Heterocyclic Compounds, 4 or More Rings (blood, metabolism, pharmacokinetics, urine)
• Humans
• Inactivation, Metabolic
• Intestinal Mucosa (metabolism)
• Intestines (drug effects)
• Mass Spectrometry (methods)
• Microsomes, Liver (drug effects, metabolism)
• Rats
• Rats, Sprague-Dawley