Regorafenib Disturbs the Metabolism of Ticagrelor Catalyzed by UDP-Glucuronosyltransferase (UGT) 2B7

Ticagrelor, approved by Food and Drug Administration (FDA), an oral reversible P2Y12 receptor inhibitor, has been demonstrated to decrease the atherosclerotic thrombosis by inhibiting the formation of new blood clots. Regorafenib is an orally administered small-molecule inhibitor of multiple protein kinases, and has been used as the anti-tumor drug towards various types of cancers. Given the possibility for the co-administration of ticagrelor and regorafenib, the inhibition of regorafenib towards ticagrelor metabolism-related enzyme UDP-glucuronosyltransferase (UGT) 2B7 was investigated. Recombinant UGT2B7-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was used as the probe reaction to phenotype the activity of UGT2B7, and was used to evaluate the inhibition of regorafenib towards the activity of UGT2B7. Regorafenib 100 mu M was firstly used as the initial screening concentration, and more than 80% activity of UGT2B7 was inhibited at this concentration (p < 0.001). Furthermore, regorafenib has been demonstrated to show concentration-dependent inhibition on the activity of UGT2B7, and the IC50 value was demonstrated to be between 1 and 5 mu M. Metabolic reaction velocity (v) was determined at multiple concentrations of 4-MU and regorafenib, and Lineweaver-Burk plot was drawn using 1/v versus 1/[4-MU] at various concentrations of regorafenib. The results showed that the intersection point was located in the vertical axis of Lineweaver-Burk plot, indicating the competitive inhibition of regorafenib towards UGT2B7. The slopes of the lines in the Lineweaver-Burk plot were calculated, and drawn versus the concentrations of regorafenib. The fitting equation of this second plot was determined to be y = 37.6x + 18.8. Based on this fitting equation, the inhibition kinetic parameter (Ki) was calculated to be 0.5 mu M. All these results indicated the potential drug-drug interaction between regorafenib and ticagrelor.