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

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Received for publication October 9, 2007.
Revised December 2, 2007.
Accepted for publication December 3, 2007.

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 IN RAT LIVER MICROSOMES

Hye Hyun Yoo 1, Hye Jin Chung 1, Jaeick Lee 2, Chang-Seok Lee 2, Min Jung Kang 3, Dong-Hyun Kim 1*

1 Korea Institute of Science and Technology 2 LG Life Science Co. 3 Korea Institute of Science and technology

* Address correspondence to: E-mail: dhkim{at}kist.re.kr

Abstract

The in vitro metabolism of LC15-0133, a novel dipeptidyl peptidase-4 (DPP-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 non-enzymatic decarboxylation of the carboxyl metabolite (M1). Non-enzymatic decarboxylation is postulated to occur due to the resonance stabilization by the oxadiazole ring attached to the tert-butyl moiety.


Key words: enzyme mechanism, metabolite identification, P450 mechanism, structure elucidation


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.
[Abstract] [Full Text] [PDF]


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