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Drug Metabolism and Disposition Fast Forward
First published on December 5, 2007; DOI: 10.1124/dmd.107.019133

0090-9556/08/3603-485-489$20.00
DMD 36:485-489, 2008

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SHORT COMMUNICATION

Enzymatic C-Demethylation of 1-[2-(5-tert-Butyl-[1,3,4] oxadiazole-2-carbonyl)-4-fluoro-pyrrolidin-1-yl]-2-(2-hydroxy-1,1-dimethyl-ethylamino)-ethanone (LC15-0133) in Rat Liver MicrosomesFormula

Hye Hyun Yoo, Hye Jin Chung, Jaeick Lee, Chang-Seok Lee, Min Jung Kang, and Dong-Hyun Kim

Doping Control Center, Korea Institute of Science and Technology, Chungryang, Seoul, Korea (H.H.Y., H.J.C., M.J.K., D.-H.K.); and Bioanalysis and Mass Spectrometry, LG Life Sciences R&D, Taejon, Korea (J.L., C.-S.L.)

The in vitro metabolism of 1-[2-(5-tert-butyl-[1,3,4] oxadiazole-2-carbonyl)-4-fluoro-pyrrolidin-1-yl]-2-(2-hydroxy-1,1-dimethyl-ethylamino)-ethanone (LC15-0133), a novel dipeptidyl peptidase-4 inhibitor, was investigated using a hepatic microsomal system. The structures of the metabolites were characterized using mass spectral analysis and by comparison with synthetic references. The in vitro incubation of LC15-0133 with rat liver microsomes resulted in the formation of six metabolites, with the major metabolic reactions being hydroxylation and carbonyl reduction. Of the metabolites, a C-demethylated metabolite (M4) was identified, but was only detected in rat liver microsomes; experimental evidence revealed that the C-demethylated metabolite was generated by nonenzymatic decarboxylation of the carboxyl metabolite (M1). Nonenzymatic decarboxylation is postulated to occur due to the resonance stabilization by the oxadiazole ring attached to the tert-butyl moiety.

Address correspondence to: Dong-Hyun Kim, Doping Control Center, Korea Institute of Science and Technology, PO Box 131, Chungryang, Seoul 136-791, Korea. E-mail: dhkim{at}kist.re.kr




This article has been cited by other articles:


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 Drug Metab. Dispos.Home page
C. Prakash, W. Wang, T. O'Connell, and K. A. Johnson
CYP2C8- and CYP3A-Mediated C-Demethylation of (3-{[(4-tert-Butylbenzyl)-(pyridine-3-sulfonyl)-amino]-methyl}-phenoxy)-acetic Acid (CP-533,536), an EP2 Receptor-Selective Prostaglandin E2 Agonist: Characterization of Metabolites by High-Resolution Liquid Chromatography-Tandem Mass Spectrometry and Liquid Chromatography/Mass Spectrometry-Nuclear Magnetic Resonance
Drug Metab. Dispos., October 1, 2008; 36(10): 2093 - 2103.
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