Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the third leading cause of cancer deaths worldwide [1]
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
Previous in vitro and in vivo studies showed that sorafenib underwent oxidative metabolism by CYP3A4 and glucuronidation by UGT1A9 into 8 metabolites [16]
Summary
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the third leading cause of cancer deaths worldwide [1]. Sorafenib has been the most effective drug in the clinical setting [2] and newer and effective drugs are necessary to clinically combat HCC. BZG was one of the novel inhibitors that potently and selectively inhibits activities of kinases including VEGFR, Flt (Fmslike tyrosine kinase), c-kit and other kinases similar to sorafenib [5, 6]. Our previous research indicated that BZG significantly inhibited Huh cell derived tumor xenografts in Balb/c nude mice [7, 8]. Studies showed relatively high concentrations of BZG in the liver and kidney providing a pharmacokinetic (PK) basis for their effective use in hepatic and renal carcinomas [9]. The in vivo metabolism and probable drug-drug interactions of BZG are unclear
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