In this study, an online electrochemistry coupling high-performance liquid chromatography-mass spectrometry (EC-HPLC-MS) technology has been developed for simulating metabolic reactions and rapid analysis of metabolites of flavone, quercetin, and rutin, which are not only widely present compounds with pharmacological activity in nature, but also have structural similarity and variability. The simulated metabolic processes of the substrates (phase I and phase II metabolism) were implemented on the surface of glassy carbon electrode (GCE) by using different electrochemical methods. After online chromatographic separation, the products were transmitted to a mass spectrometer for detection, in order to speculate relevant reaction pathways and structural information of the reaction product. The main metabolites, including methylation, hydroxylation, hydrolysis, and conjugation reaction products, had been successfully identified through the designed in situ hyphenated technique. Furthermore, compared with metabolites produced by in vitro incubation of rat liver microsomes, it was found that the products of electrochemical simulated metabolism were more abundant with diverse metabolic pathways. The results indicated that the proposed method exhibited advantages in the sample pretreatment process and detection cycle without compromising the reliability and accuracy of the results. Graphical
Yan Lou,Wenqi Qiu,Zhe Wu,Qian Wang,Yunqing Qiu,Su Zeng
We previously showed that BZG is a novel multitarget kinase inhibitor, which inhibited hepatocellular carcinoma in vivo and in vitro . In the present study, we used ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS) to characterize BZG and its metabolites generated in vivo . The probable metabolic mechanism was further confirmed by analysis of Phase I and Phase II metabolism in liver microsomes and with recombinant enzymes. In addition, the binding affinities of BZG metabolites to vascular endothelial growth factor receptor 2 (VEGFR2) were predicted using electronic high throughput screening (eHiTS). The results showed that BZG underwent phase I and phase II metabolism. We detected 11 BZG metabolites and identified hydroxylation, glucuronation, acetylation, sulfonation and degradation as the major metabolic processes in vivo and in vitro . Five of the eleven metabolites showed highly favorable eHiTS energy scores that were lower than sorafenib. Knowledge of the in vivo metabolic pathways of BZG and its binding affinities to VEGFR2 will be beneficial for further clinical development of BZG.
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