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In vitro metabolism of olaparib in liver microsomes by liquid chromatography/electrospray ionization high‐resolution mass spectrometry
Author(s) -
Wang Li,
Wang Meixia
Publication year - 2020
Publication title -
rapid communications in mass spectrometry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.528
H-Index - 136
eISSN - 1097-0231
pISSN - 0951-4198
DOI - 10.1002/rcm.8575
Subject(s) - chemistry , olaparib , chromatography , metabolite , electrospray ionization , hydroxylation , mass spectrometry , microsome , resolution (logic) , tandem mass spectrometry , biochemistry , in vitro , enzyme , poly adp ribose polymerase , polymerase , artificial intelligence , computer science
Rationales Olaparib is a Poly (ADP‐ribose) Polymerase (PARP) inhibitor which has been developed as an anti‐cancer agent. The purpose of this study was to characterize the metabolites of olaparib from liver microsomes and to reveal the interspecies differences between animals and humans. Methods Olaparib (20 μM) was incubated with different species of liver microsomes at 37°C for 1 h in the presence of NADPH. The incubation samples were analyzed by liquid chromatography/electrospray ionization high‐resolution mass spectrometry (LC/ESI‐HRMS) operated in positive ion mode. The metabolites were characterized by accurate masses, MS 2 spectra and retention times. Results A total of 12 metabolites were detected and the structures of the metabolites were characterized based on their accurate masses, fragment ions and retention times. Four metabolites, i.e., M1, M10, M11 and M12, were unambiguously identified by using reference standards. The metabolic pathways of olaparib included hydroxylation, bis‐hydroxylation, hydrolysis, dealkylation, dehydrogenation, and alcohol oxidation. Conclusions Compared with animal species, no human‐specific metabolite was found in HLM. Dog also had a closer metabolic profile to humans. This study will be helpful for a better understanding of the species difference in pharmacokinetics/pharmacodynamics.