Effect of Flavonoids and CYP3A4 Variants on Midostaurin Metabolism

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 mu M level. After co-administration of midostaurin and myricetin, the plasma concentration of midostaurin's primary metabolite CGP62221 was reduced corresponding to myr-icetin 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 mu M and 90.99 +/- 16.13 mu M, respectively. Collectively, our data demonstrated that flavonoids, particularly myricetin, can inhibit the metabolism of mid-ostaurin. Additionally, CYP3A4 genetic polymorphism may contribute to stratification of midostaurin blood exposure.