Inhibition of SN-38 glucuronidation by gefitinib and its metabolite

Drug combinations including irinotecan and gefitinib have been evaluated in clinical trials. SN-38 is the active metabolite of irinotecan, and the increase in its concentration due to drug interactions will result in increased clinical toxicity. We aimed to investigate the effects of gefitinib and its predominant metabolite observed in human plasma, O-desmethyl-gefitinib (DMG), on SN-38 glucuronidation. Our data indicated that both gefitinib and DMG are potent inhibitors of SN-38 glucuronidation via UGT1A1 inhibition. It is predicted from in vitro data that gefitinib administered at 700 mg/day may result in about 149 % increase in SN-38 AUC, but there is no significant effects on SN-38 AUC at lower concentrations. Our prediction study provides a basis for design of clinical studies for the development and optimization of this combination.