Abstract
The metabolic profile of the potent hypoglycemic agent, (2S)-pterosin A (1), in rat urine via intragastrical oral administration was investigated. In total, 19 metabolites (M1–M19) were identified. Among these, 16 metabolites were characterized by high-performance liquid chromatography solid-phase extraction-tube transfer-NMR, and seven metabolites were further isolated from the treated urine to enable further structural determination. Twelve of these are new compounds. The phase I metabolites of 1 were formed via various oxidations at positions C-3, C-10, C-12, C-13, or C-1 followed by decarboxylation of C-10 or C-14, and lactonization at C-12/C-14 or C-14/C-12. The phase II metabolites were glucuronide conjugates from the parent compound or phase I metabolites. The major metabolites were found to be (2S)-14-O-glucuronylpterosin A (M9), (2S)-2-hydroxymethylpterosin E (M14), and (±)-pterosin B (M19). Quantitative HPLC analysis of metabolites, based on similar UV absorption and use of the regression equation of 1, indicated that ∼71% 1 was excreted as metabolites in rat urine.
Footnotes
This work was supported by the National Science Council, Taiwan [Grants NSC98-2323-B-002-001, NSC99-2323-B-002-010].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
ABBREVIATIONS:
- HPLC
- high-performance liquid chromatography
- SPE
- solid-phase extraction
- TT
- tube transfer
- RP
- reverse-phase
- DAD
- diode array detector
- HRESIMS
- high-resolution electrospray ionization mass spectrometry
- MS
- mass spectrometry
- NOEDS
- nuclear Overhauser effect difference spectrum
- HSQC
- heteronuclear single quantum correlation
- HMBC
- heteronuclear multiple bond coherence
- FA
- formic acid
- GlcUA
- glucuronyl
- LC15-0133
- 1-[2-(5-tert-butyl-[1,3,4]oxadiazole-2-carbonyl)-4-fluoro-pyrrolidin-1-yl]-2-(2-hydroxy-1,1-dimethylethylamino)-ethanone.
- Received February 10, 2012.
- Accepted May 15, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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