Bio-activation of simeprevir in liver microsomes and characterization of its glutathione conjugates by liquid chromatography coupled to ultrahigh-resolution quadrupole time-of-flight mass spectrometry
| Autor: | Mohamed M.Y. Kaddah, Ramona Oehme, Claudia Birkemeyer, Susan Billig |
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| Rok vydání: | 2021 |
| Předmět: |
Simeprevir
010402 general chemistry Mass spectrometry 01 natural sciences Biochemistry Analytical Chemistry Adduct Hydrolysis chemistry.chemical_compound Fragmentation (mass spectrometry) Tandem Mass Spectrometry Animals Humans Dehydrogenation Chromatography Chemistry 010401 analytical chemistry Organic Chemistry General Medicine Glutathione Rats 0104 chemical sciences Triple quadrupole mass spectrometer Microsomes Liver Chromatography Liquid |
| Zdroj: | Journal of Chromatography A. 1645:462095 |
| ISSN: | 0021-9673 |
| DOI: | 10.1016/j.chroma.2021.462095 |
| Popis: | Liquid chromatography coupled to a triple quadrupole and, alternatively, to an ultrahigh-resolution quadrupole time-of-flight (UHR-QqTOF) mass spectrometers was used to collect qualitative and quantitative information from incubations of the anti-hepatitis C drug simeprevir with human and rat liver microsomes, respectively, supplemented with NADPH and glutathione. For this, different chromatographic methods using two different chromatographic columns, Kinetex® 2.6 µm C18 (50 × 3 mm) and Atlantis T3 (100 A, 3 µm, 4.6 mm × 150 mm), have been employed. For determination and structural characterization of the reactive metabolites, we used information obtained from high-resolution mass spectrometry, namely accurate mass data to calculate the elemental composition, accurate MS/MS fragmentation patterns for confirmation of structural proposals, and the high mass spectral resolution to eliminate false-positive peaks. In this study, the use of high-resolution mass spectrometry (HR-MS) enabled the identification of 19 simeprevir metabolites generated by O- respectively N-demethylation, oxidation, dehydrogenation, hydrolysis, and formation of glutathione conjugates. The in silico study provides insights into the sites of simeprevir most amenable to reactions involving cytochrome P450. The developed methods have been successfully applied to analyze simeprevir and its metabolites simultaneously; based on this data, potential metabolic pathways of simeprevir are discussed. In general, the obtained results demonstrate that simeprevir is susceptible to form reactive simeprevir-glutathione adducts and cyclopropansulfonamide, which may explain the implication of simeprevir in idiosyncratic adverse drug reactions (IADRs) or hepatotoxicity. |
| Databáze: | OpenAIRE |
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