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J Mass Spectrom. 2013 Sep;48(9):1019-31. doi: 10.1002/jms.3247.

Revealing the metabolic sites of atazanavir in human by parallel administrations of D-atazanavir analogs.

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1
Concert Pharmaceuticals, Inc., 99 Hayden Avenue, Suite 500, Lexington, MA, 02421, USA.

Abstract

Atazanavir (Reyataz(®)) is an important member of the HIV protease inhibitor class. Because of the complexity of its chemical structure, metabolite identification and structural elucidation face serious challenges. So far, only seven non-conjugated metabolites in human plasma have been reported, and their structural elucidation is not complete, especially for the major metabolites produced by oxidations. To probe the exact sites of metabolism and to elucidate the relationship among in vivo metabolites of atazanavir, we designed and performed two sets of experiments. The first set of experiments was to determine atazanavir metabolites in human plasma by LC-MS, from which more than a dozen metabolites were discovered, including seven new ones that have not been reported. The second set involved deuterium labeling on potential metabolic sites to generate D-atazanavir analogs. D-atazanavir analogs were dosed to human in parallel with atazanavir. Metabolites of D-atazanavir were identified by the same LC-MS method, and the results were compared with those of atazanavir. A metabolite structure can be readily elucidated by comparing the results of the analogs and the pathway by which the metabolite is formed can be proposed with confidence. Experimental results demonstrated that oxidation is the most common metabolic pathway of atazanavir, resulting in the formation of six metabolites of monooxidation (M1, M2, M7, M8, M13, and M14) and four of dioxidation (M15, M16, M17, and M18). The second metabolic pathway is hydrolysis, and the third is N-dealkylation. Metabolites produced by hydrolysis include M3, M4, and M19. Metabolites formed by N-dealkylation are M5, M6a, and M6b.

KEYWORDS:

atazanavir; deuterium labeling; high performance liquid chromatography; human immunodeficiency virus; metabolic pathway; metabolite identification; protease inhibitor; tandem mass spectrometry

PMID:
24078243
DOI:
10.1002/jms.3247
[Indexed for MEDLINE]
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