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Determination and structural characterization of ravidasvir metabolites by LC coupled to triple quadrupole linear ion trap MS: Application to pharmacokinetics and phase I metabolism in rats
Author(s) -
Kaddah Mohamed Mohamed Yousri,
Talaat Wael,
El Demellawy Maha A.
Publication year - 2021
Publication title -
biomedical chromatography
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.4
H-Index - 65
eISSN - 1099-0801
pISSN - 0269-3879
DOI - 10.1002/bmc.5146
Subject(s) - chemistry , pharmacokinetics , metabolite , chromatography , quadrupole ion trap , metabolic pathway , metabolism , drug metabolism , mass spectrometry , ion trap , pharmacology , biochemistry , medicine
Hepatitis C virus (HCV) is an infectious disease that has become a global clinical issue because of its significant morbidity and mortality. Novel anti‐hepatitis C drugs are continuously developed to decrease the pervasiveness of the infection globally. A synthetic ravidasvir, benzimidazole‐naphthylene‐imidazole derivatives, has been used as an anti‐HCV drug. This study determined the metabolites of ravidasvir and its pharmacokinetics in rats using information‐dependent acquisition and multiple reaction monitoring scanning modes in linear ion trap LC–MS/MS instrument, respectively. Two time‐programming linear‐gradient chromatographic methods were employed using a Kinetex C 18 column (50 × 3 mm, 2.6 μm) and a Luna HILIC column (100 × 4.6 mm, 3 μm) for the qualitative and quantitative determination of ravidasvir and its metabolites, respectively. In silico prediction where sites in a molecule are susceptible to metabolism by cytochrome P 450 was implemented, which helped in proposing the metabolic pathway of ravidasvir. The most dominant metabolite in rat liver microsomal samples was oxidative ravidasvir, where one O ‐demethylated metabolite and eight isomers of the oxidative ravidasvir metabolites were identified. The study provides essential data for proposing the metabolic pathway and successfully applied it to determine the pharmacokinetics of ravidasvir in rat plasma.