Pharmacokinetic study of a novel SHP2 derivative NC-55-122 in rats and its metabolites in vivo
To investigate the pharmacokinetic characteristics and metabolites of Src homology 2 region-containing protein tyrosine phosphatase 2(SHP2)protein inhibitor in SD rats,a triazole quinolinone based derivative NC-55-122 was utilized.Firstly,rats were randomly divided into groups and given compound NC-55-122 intragastric and intravenous administration,respectively.Blood samples were collected at different time points.Taking carbmazepine as the internal standard,ultra-high performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)was used to determine the concentration of NC-55-122 in rats,and the methodology was verified.DAS 2.0 software was used to calculate the main pharmacokinetic parameters,and GraphPad Prism 8.0.1 software was used to plot the blood concentration-time curve.At the same time,UPLC-Q-TOF/MS was established to analyze plasma samples,and UNIFI metabolite prediction software was used to analyze metabolites after oral gavage and intravenous injection.The linear range of the mass concentration of compound NC-55-122 was from 1 ng·mL-1 to 1 600 ng·mL-1,and the linear relationship was good.The matrix effect,extraction recovery,precision,accuracy and stability were investigated in this linear range,which met the requirements of biological analysis.Secondly,the analysis of pharmacokinetic parameters showed that the oral bioavailability of the compound was low,with F％=3.09％,indicating that the compound was absorbed slowly in vivo.Finally,five possible metabolites were deduced by analyzing the ion flow diagram and combining UNIFI software.The detection method established in this experiment is highly sensitive,specific,rapid and efficient,which is suitable for the determination of the blood concentration of compound NC-55-122 in rats and the analysis of metabolites,and lays a foundation for the structural modification and druggability evaluation of the later anti-tumor drug NC-55-122.All animal experiments were approved by the Experimental Animal Ethics Committee of Guizhou Medical University(approval number:2200823).
anti-tumorSrc homology 2 region-containing protein tyrosine phosphatase 2pharmacokineticsmetabolite analysis
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