Identification And Characterization Of Drug-drug Interactions Of UDP-glucuronosyltransferases Substrates

Drug combinations are commonly used in clinical practice,and increasing attention is paidto drug-drug interactions(DDI).There are a variety of mechanisms of drug interactions,among which the interactions based on metabolic enzymes are the most important causes of DDI.However,traditionally,people pay more attention to DDI mediated by cytochrome P450 enzyme system,and DDI by UDP-glucuronosyltransferases(UGT)have been neglected.UGT are the most important enzymes involved in Phase II metabolism of human,which are widely expressed in human liver,kidney and gastrointestinal tract.In recent years,UGT-mediated DDI are of growing concern.Considering the complexity of clinical trials and species differences,in vitro strategy with humanized UGT to evaluate UGT related DDI risk has become the current research trend,and researchers have begun to try to predict the in vivo drug interaction potential with various prediction models from in vitro data.The purpose of this study was to explore the UGT mediated drug interactions from two aspects: experimental and mathematical prediction models.First of all,in view of the fact that the small molecule anti-cancer drug gefitinib can inhibit UGT1A1 mediated 4-methylumbelliferone glucuronidation in our previous study,and gefitinib and irinotecan have been combinated for the treatment of colon cancer,lung cancer,neuroblastoma and other tumors,the DDI potential of gefitinib and irinotecan was evaluated and its possible mechanism was studied.Our study found that gefitinib and its phase I metabolite Odemethylation of gefitinib(DMG)were strong inhibitors of SN-38,the pharmacological active metaboliteof irinotecan,glucuronidation mediated by UGT1A1.Gefitinib could competitively inhibit SN-38 glucuronidation in both human liver microsomes and recombinant human UGT1A1,with a Ki value of 3.0±0.4 and 4.5±0.4 μM,respectively;DMG is a mixed type inhibitor,with a Ki value of 8.2±0.9 μM and 8.0±1.2 μM,α is 3.7 and 1.9,respectively.The combination of gefitinib and irinotecan may lead to clinically significant DDI.Secondly,in view of the inaccuracy of the current existing DDI prediction models and the over simplification of the key factors,especially the neglection of structure characteristics of UGT,which are located in the inner side of the endoplasmic reticulum in cells,the current research optimizedthe prediction models of UGT-mediated DDI potential and oral bioavailability in intestinal tract.The models for prediction of the bioavailability of UGT substrates,and of the DDI risk when UGT inhibitors were simultaneously administrated were established.The accuracy assessment with clinical data showed that the RMSE value(0.165)and AFE(1.077)of the new models were closer to the true values,compared with the reported models with RMSE value(0.256)and AFE(0.819).