International Journal of Frontiers in Medicine, 2024, 6(9); doi: 10.25236/IJFM.2024.060904.
Liang Tan1,2,3, Shu Zhang3, Xiaochuan Li3, Lihua Qin1,2,3, Xiaoqun Duan1,2
1College of Pharmacy, Guilin Medical University, Guilin, Guangxi, 541004, China
2College of Biomedical Industry, Guilin Medical University, Guilin, Guangxi, 541004, China
3Suzhou Xuhui Analysis Co., Ltd., No. 168 Yuanfeng Road, Kunshan, Jiangsu, 215300, China
VT204 is a KRASG12C inhibitor for the treatment of non-small cell lung cancer, which has good structural characteristics and pharmacological effects. It has become an essential part of preclinical metabolic research to determine the main subtypes of metabolic enzymes by in vitro study of metabolic enzyme phenotypes.In this study, the main CYP450 isoenzymes involved in VT204 metabolism were investigated by chemical inhibition method and recombinant enzyme method. Two incubation systems were established respectively, and LC-MS/MS technology was used to detect the peak area ratio of VT204 and CYP450 enzyme-specific metabolites and substrates in the incubation solution to internal standard terphenadine, respectively. According to the calculation, ketoconazole (CYP3A4 inhibitor) showed a high inhibition of VT204 by chemical inhibition method (85.7%), followed by Montelukast (CYP2C8 inhibitor, 49.6%) and sulfameprazole (CYP2C9 inhibitor, 17.6%).The residual rate was 19.9% for CYP3A4 and 80.4% for CYP2C8 by recombinant enzyme method. Results Preliminary identification of CYP3A4 as the main metabolic enzyme of VT204, CYP2C8 and CYP2C9 may be involved in the metabolic process of VT204, the results can provide a reference for further study of the metabolism of VT204 in vivo and reasonable clinical compatibility.
VT204, chemical inhibition, recombinant enzymatic method, LC-MS/MS
Liang Tan, Shu Zhang, Xiaochuan Li, Lihua Qin, Xiaoqun Duan. Phenotyping of VT204 metabolic enzymes in human liver microsomes. International Journal of Frontiers in Medicine (2024), Vol. 6, Issue 9: 20-28. https://doi.org/10.25236/IJFM.2024.060904.
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