杨梅素
CYP3A4型
米多司他林
药理学
化学
IC50型
体内
新陈代谢
生物化学
细胞色素P450
生物
体外
内科学
医学
遗传学
槲皮素
山奈酚
白血病
抗氧化剂
作者
Ren-ai Xu,Qing Li,Nanyong Gao,Jing Wang,Xin-yue Li,Feng Ye,Jinhuan Ni,Guoxin Hu,Guoxin Hu
标识
DOI:10.1016/j.fct.2023.113669
摘要
The objective of this study was to determine the effect of flavonoids on midostaurin disposition considering co-administration and metabolic enzyme gene polymorphism. Enzymatic incubation assays were performed in vitro, while in vivo experiments were conducted in Sprague-Dawley rats. The analytes were determined via UPLC-MS/MS. We found that myricetin was the most potent among the investigated 10 flavonoids in suppressing the metabolism of midostaurin, with an IC50 at a low μM level. After co-administration of midostaurin and myricetin, the plasma concentration of midostaurin's primary metabolite CGP62221 was reduced corresponding to myricetin exposure. Furthermore, CYP3A4 homologous rat protein CYP3A2 was reduced significantly in the co-administration group. Thereafter, the kinetic parameters of 23 recombinant human CYP3A4 variants were determined using midostaurin. The relative intrinsic clearance varied from 269.63% in CYP3A4.29-8.95% in CYP3A4.17. In addition, the inhibitory potency of myricetin was substantially different for CYP3A4.29 and CYP3A4.17 compared with wild type, with IC50 values of 9.85 ± 0.27 μM and 90.99 ± 16.13 μM, respectively. Collectively, our data demonstrated that flavonoids, particularly myricetin, can inhibit the metabolism of midostaurin. Additionally, CYP3A4 genetic polymorphism may contribute to stratification of midostaurin blood exposure.
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