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Revealing the metabolic sites of atazanavir in human by parallel administrations of D‐atazanavir analogs
Author(s) -
Cheng Changfu,
Vedananda Sunanda,
Wu Lijun,
Harbeson Scott,
Braman Virginia,
Tung Roger
Publication year - 2013
Publication title -
journal of mass spectrometry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 121
eISSN - 1096-9888
pISSN - 1076-5174
DOI - 10.1002/jms.3247
Subject(s) - atazanavir , chemistry , metabolite , metabolic pathway , biochemistry , metabolism , human immunodeficiency virus (hiv) , medicine , family medicine , viral load , antiretroviral therapy
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. Copyright © 2013 John Wiley & Sons, Ltd.