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Xenobiotica
the fate of foreign compounds in biological systems
Volume 44, 2014 - Issue 5
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Animal Pharmacokinetics and Metabolism

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

, , , , , & show all
Pages 455-464 | Received 05 Sep 2013, Accepted 07 Oct 2013, Published online: 05 Nov 2013
 

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.

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