In Vitro Identification of Potential Metabolites of Plinabulin (NPI 2358) in Hepatic Preparations Using Liquid Chromatography-Ion Trap Mass Spectrometry.
Nasser S Al-ShakliahAdnan A KadiRashad Al-SalahiA F M Motiur RahmanPublished in: ACS omega (2022)
Plinabulin ( 1 , NPI2358), a vascular disrupting agent (VDA) molecule, is a synthetic analogue of the natural product phenylahistin ( 2 , NPI 2350), which is isolated from Aspergillus ustus . Evaluation of the in vitro metabolic profile of VDA plinabulin using human liver microsomes (HLMs) and HepaRG Cells Cryopreserved is described. HLMs and HepaRG Cells Cryopreserved were prepared in-house and incubated with plinabulin according to published methodologies. The incubated mixtures were analyzed by liquid chromatography-ion trap mass spectrometry to identify possible metabolic products. The incubated plinabulin ( 1 ) revealed the presence of several peaks representing 19 tentative metabolites in HLMs and HepaRG Cells Cryopreserved in the presence of NADPH (nicotinamide adenine dinucleotide phosphate) and in the absence of NADPH-generating system, respectively. However, in NADPH absence, no metabolites and microsomes were generated for 1 in incubated HLMs, indicating a likely involvement of CYP450 enzymes in the metabolism. The metabolite structures, obtained from HLMs and HepaRG Cells Cryopreserved incubations, were elucidated by LC-MS/MS fragmentation study. Seventeen phase-I metabolites were proposed to be the results of isomerization, hydroxylation, hydration, and oxygenation of 1 in HLMs and two isomeric phase-II sulfate conjugate metabolites of 1 in HepaRG Cells Cryopreserved incubation.
Keyphrases
- induced apoptosis
- mass spectrometry
- liquid chromatography
- cell cycle arrest
- ms ms
- phase ii
- clinical trial
- systematic review
- high resolution
- high resolution mass spectrometry
- randomized controlled trial
- cell proliferation
- signaling pathway
- open label
- cord blood
- simultaneous determination
- bone marrow
- tandem mass spectrometry
- high performance liquid chromatography
- capillary electrophoresis
- solid phase extraction