Inhibitory effects of infigratinib and its pharmacologically active metabolites on CYPs and UGTs in rat liver microsomes
10.13699/j.cnki.1001-6821.2024.16.014
- VernacularTitle:英菲格拉替尼及其活性代谢产物对大鼠肝微粒体中CYPs和UGTs的抑制作用
- Author:
Shi-Yu ZHAO
1
;
Shuai-Bing LIU
;
Xia YAO
;
Xin TIAN
Author Information
1. 郑州大学第一附属医院药学部,河南郑州 450052
- Keywords:
infigratinib;
metabolite;
cytochrome P450;
UDP-glucuronosyltransferases;
enzyme inhibition
- From:
The Chinese Journal of Clinical Pharmacology
2024;40(16):2368-2372
- CountryChina
- Language:Chinese
-
Abstract:
Objective To evaluate the inhibitory effects of infigratinib and its pharmacologically active metabolites,BHS697 and CQM157,on cytochrome P450(CYPs)and UDP-glucuronosyltransferases(UGTs)in rat liver microsomes.Methods By adopting in vitro incubation method,the tested compounds(infigratinib,BHS697 or CQM157)and rat liver microsomes were incubated with the specific probe substrates of CYP2B6,CYP2C8,CYP2C9,CYP2C19,CYP2D6,CYP3 A4,respectively,or the specific probe substrates of UGT1A1,UGT1A3,UGT1A6,UGT1A9,UGT2B7,respectively.The production of characteristic metabolites was detected by high performance liquid chromatography-tandem mass spectrometry.The half maximal inhibitory concentration(IC50)and inhibition constant(Ki)were calculated by GraphPad Prism 8.0.Results Infigratinib,BHS697 and CQM157 weakly inhibited CYP2B6,CYP2C8,CYP2C9,CYP2C19,CYP2D6,CYP3 A4 and UGT1A6,UGT2B7 in rat liver microsomes,with IC50 values all more than 10 μmol·L-1,and moderately inhibited UGT1Al with IC50 values of 2.70,3.17,7.43 μmol·L-,respectively.Infigratinib had a moderate inhibitory effect on UGT1A9 and CQM157 had a moderate inhibitory effect on UGTIA3,with IC50 values of 5.61 and 9.57 μmol·L-1,respectively.The reversible inhibition analysis showed that infigratinib,BHS697 and CQM157 all non-competitively inhibited UGTIA1,with Ki values of 1.83,2.51 and 5.84 μmol·L-1,respectively.Conclusion Infigratinib had moderate inhibitory effects on UGT1A1 and UGT1A9 in rat liver microsomes and its pharmacologically active metabolites,BHS697 and CQM157,also had moderate inhibitory effects on UGT1A1.
