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Comparative bioactivation of the novel anti-tuberculosis agent PA-824 in Mycobacteria and a subcellular fraction of human liver

Citation

Dogra, M and Palmer, BD and Bashiri, G and Tingle, MD and Shinde, SS and Anderson, RF and O'Toole, RF and Baker, EN and Denny, WA and Helsby, NA, Comparative bioactivation of the novel anti-tuberculosis agent PA-824 in Mycobacteria and a subcellular fraction of human liver, British Journal of Pharmacology, 162, (1) pp. 226-236. ISSN 0007-1188 (2011) [Refereed Article]

DOI: doi:10.1111/j.1476-5381.2010.01040.x

Abstract

BACKGROUND AND PURPOSE: PA-824 is a 2-nitroimidazooxazine prodrug currently in Phase II clinical trial for tuberculosis therapy. It is bioactivated by a deazaflavin (F(420) )-dependent nitroreductase (Ddn) isolated from Mycobacterium tuberculosis to form a des-nitro metabolite. This releases toxic reactive nitrogen species which may be responsible for its anti-mycobacterial activity. There are no published reports of mammalian enzymes bioactivating this prodrug. We have investigated the metabolism of PA-824 following incubation with a subcellular fraction of human liver, in comparison with purified Ddn, M. tuberculosis and Mycobacterium smegmatis.

EXPERIMENTAL APPROACH: PA-824 (250 M) was incubated with the 9000 g supernatant (S9) of human liver homogenates, purified Ddn, M. tuberculosis and M. smegmatis for metabolite identification by liquid chromatography mass spectrometry analysis.

KEY RESULTS: PA-824 was metabolized to seven products by Ddn and M. tuberculosis, with the major metabolite being the des-nitro product. Six of these products, but not the des-nitro metabolite, were also detected in M. smegmatis. In contrast, only four of these metabolites were observed in human liver S9; M3, a reduction product previously proposed as an intermediate in the Ddn-catalyzed des-nitrification and radiolytic reduction of PA-824; two unidentified metabolites, M1 and M4, which were products of M3; and a haem-catalyzed product of imidazole ring hydration (M2).

CONCLUSIONS AND IMPLICATIONS: PA-824 was metabolized by des-nitrification in Ddn and M. tuberculosis, but this does not occur in human liver S9 and M. smegmatis. Thus, PA-824 was selectively bioactivated in M. tuberculosis and there was no evidence for 'cross-activation' by human enzymes.

Item Details

Item Type:Refereed Article
Keywords:metabolism of PA-824; Mycobacterium tuberculosis; nitroimidazoles
Research Division:Medical and Health Sciences
Research Group:Medical Microbiology
Research Field:Medical Bacteriology
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Infectious Diseases
Author:O'Toole, RF (Dr Ronan O'Toole)
ID Code:95701
Year Published:2011
Web of Science® Times Cited:7
Deposited By:Medicine (Discipline)
Deposited On:2014-10-07
Last Modified:2017-11-02
Downloads:0

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