Drug Interaction Mechanism And Risk Prediction Of Combination Ginseng With Irinotecan

Ginseng is a traditional Chinese herb medicine with many pharmacological activities.It is widely used in the world,accounting for 28%of the world's herbal consumption.In recent years,the frequency of clinical use of anti-cancer drugs has increased greatly,and the ginseng-related herbal-prescription drug interaction(HDI)has also received increasing attention.Irinotecan is a clinical first-line drug for the treatment of colorectal cancer,but its narrow therapeutic window and high toxicity limit its clinical application.the key step in determining the severity of adverse reactions to irinotecan are UDP-glucuronyltransferase 1A1(UGT1A1)mediated SN-38 glucose Aldolization and?-glucuronidase(?-GUS)-mediated hydrolysis of SN-38glucuronide(SN-38G).Previous studies have found that ginsenoside,the main pharmacological active ingredient of ginseng,have inhibitory effects on various UGTs,which suggested that the combination of irinotecan with ginseng in humans may cause clinically significant HDI.This study aims to use in vitro experiments,molecular docking simulation and extracorporeal data to in vivo parameter extrapolation(IVIVE)technology to systematically evaluate the inhibitory effect of ginsenosides on the metabolic process of SN-38,reveal its possible molecular mechanisms,and participate in clinical intervention.The possibility of HDI when combin ginseng and irinotecan is predicted.First,based on the basic assumptions of pharmacology,the premise of the drug's function is that it can reach the drug target site in vivo and combine with the drug target.We use Discovery Studio software to penetrate the membrane abilities and absorb the human intestinal tractof 135 ginseng saponins.Results showed that few saponins such as PPT and CK have a certain membrane permeability.Secondly,the influence of a series of naturally occurring ginsenosides and their intestinal metabolites on SN-38,the active metabolite of irinotecan,glucuronidation were investigated by using human liver microsomes and recombinant UGT1A1.The study found that 12 kinds of ginsenosides showed different degrees of inhibition on SN-38glucuronidation,and the inhibition decreased with the increase of the number of sugar chains on ginsenosides.PPT showed the strongest inhibition,enzyme power Studies have shown that PPT competitively inhibits UGT1A1-catalyzed SN-38 glucuronidation with K_i values of 12.36±1.41?M(enzyme source:HLMs)and 4.23±0.45?M(enzyme source:UGT1A1).Thirdly,the possible mechanism of inhibition of SN-38 glucuronidation by PPT was explored by molecular docking technique,and key amino acid residues of interaction were identified.The study found that the inhibitor PPT competes with the substrate SN-38 for the same binding site of UGT1A1.Fourth,in view of the fact that SN-38G can be hydrolyzed by?-GUS,we investigated the effects of 12 ginsenosides on?-GUS activity.Studies have found that ginsenosides F2 and R can weakly inhibit?-GUS activity.In view of the low concentration of these saponins in the intestine after oral administration of ginseng products,the possibility of ginseng inhibiting?-GUS activity is low.Finally,the risk of drug interaction between ginsenosides and irinotecan was predicted by the IVIVE method.The results showed that when humans were used in combination irinotecan with ginseng may induce clinically significant drug interactions and increase drug dysfunction through the inhibition of SN-38glucuronidation by,the intestinal metabolite of ginseng,PPT.