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]
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 µM) 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 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 Group:||Clinical Health (Organs, Diseases and Abnormal Conditions)|
|Objective Field:||Infectious Diseases|
|Author:||O'Toole, RF (Dr Ronan O'Toole)|
|Web of Science® Times Cited:||7|
|Deposited By:||Medicine (Discipline)|
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