Journal
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
Volume 125, Issue 4, Pages 337-344Publisher
WILEY
DOI: 10.1111/bcpt.13246
Keywords
genetic polymorphism; metabolism; regorafenib; regorafenib-N-oxide
Categories
Funding
- Ministry of Science and Technology [2017ZX09304026] Funding Source: Medline
Ask authors/readers for more resources
Aim Regorafenib is a tyrosine kinase inhibitor that is mainly metabolized by CYP3A4. The genetic polymorphism of CYP3A4 would contribute to differences in metabolism of regorafenib. Previously, we had discovered several novel CYP3A4 variants. However, the catalytic characteristics of these 27 CYP3A4 variants on oxidizing regorafenib have not being determined. The purpose of this study was to investigate the catalytic characteristics of 27 CYP3A4 protein variants on the oxidative metabolism of regorafenib in vitro. Method Wild-type CYP3A4.1 or other variants was incubated with 0.5-20 mu mol/L regorafenib for 30 minutes. After sample processing, regorafenib-N-oxide, a primary metabolite, was detected by ultra-performance liquid chromatography-tandem mass spectrometry system. Result CYP3A4.20 had no detectable enzyme activity compared with wild-type CYP3A4.1; five variants (CYP3A4.5, .16, .19, .24, .29) exhibited similar clearance value with CYP3A4.1; four variants (CYP3A4.14, .15, .28, .31) displayed increased enzymatic activities, while remaining variants showed markedly decreased intrinsic clearance values. Conclusion This study is the first to investigate the function of 27 CYP3A4 protein variants on the metabolism of regorafenib in vitro, and it may provide some valuable information for further research in clinic.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available