Drug-drug Interaction in the Treatment of Gastrointestinal Tumors

Gastrointestinal cancer refers to the malignant conditions of the gastrointestinal tract (GI tract) and accessory organs of digestion, and gastrointestinal cancer is threatening more and more patients. Trametinib is an approved anti-cancer drug also exhibiting efficiency towards gastrointestinal cancer. This study aims to investigate the effect of trametinib on UDP-glucuronosyltransferase (UGT) 2B7, trying to indicate the potential drug-drug interaction (DDI). Both in vitro human liver microsomes (HLMs)-catalyzed zidovudine (AZT) glucuronidation and recombinant UGT2B7-catalyzed 4-Methylum-belliferone (4-MU) glucuronidation were used to investigate the inhibition of trametinib on the activity of UGT2B7. The results showed that trametinib strongly inhibited both HLMs-catalyzed AZT glucuronidation and UGT2B7-catalyzed 4-MU glucuronidation. Furthermore, using recombinant UGG2B7-catalyzed 4-MU glucuronidation as the probe reaction, the half inhibition concentration (IC50) was calculated to be between 5 and 10 mu M. Lineweaver-Burk plot showed that the intersection point was located in the vertical axis, indicating the competitive inhibition of trametinib towards UGT2B7. The fitting equation was y = 124x + 551.3. Using this equation, the inhibition kinetic parameter (Ki) was calculated to be 4.4 mu M. Based on the in vitro-in vivo extrapolation (IVIVE) evaluation standard ([I]/Ki > 0.1), the threshold value for the plasma exposure of trametinib to induce DDI was calculated to be 0.44 mu M. In conclusion, all these results helpful for understanding the drug-drug interaction risk between trametinib and drugs mainly undergoing UGT2B7-catalyzed glucuronidation metabolism.