Based On The Intestinal Transport Protein And Drug Metabolizing Enzymes, The Intestinal Absorption Mechanism Of The Diterpene Alcohol Esters In Stephanotis Was Studied

Objective:Based on the efflux transporters and drug metabolizing enzymes study Euphorbia Factor L1,L2,L3 in the intestinal absorption and metabolism,and clarify the mechanism of absorption and metabolism,so as to provide a scientific basis study of the three compounds in the gut Toxic.Method:Through Caco-2 cell monolayer to study the absorption and transportation of Euphorbia Factor L1,L2,L3.Determination the concentration of Euphorbia Factor L1,L2,L3 with HPLC-MS.Investigateing the effects of inhibitor of P-glycoprotein protein(P-gp),multi drug resistance protein(MRP2)and breast cancer resistance protein(BCRP)on absorption of the three compounds.2,Through rat intestinal perfusion technique to study the absorption in the intestine of Euphorbia Factor L1,L2,L3,and determinated the concentration of Euphorbia Factor L1,L2,L3 with HPLC.Investigateing the effects of inhibitor of P-glycoprotein transporter protein(P-gp),multidrug resistance protein(MRP2)to the absoption of the three compounds.3,Through the intestinal microsomes incubation in vitro studing Euphorbia Factor L1,L2,L3 metabolism in the gut.Results:1,By the Euphorbia Factor L1,L2,L3 transport studies on Caco-2 cell monolayer model,the results shows that Euphorbia Factor L1 absorbed in the intestine was medium,its transmembrane transport is major of passive transport process-based,with a concentration and time dependent,there is active transport by P-gp-mediated,Euphorbia Factor L1,L2,L3 may be the P-gp substrate,MRP2 and BCRP inhibitor had no effect on the transportation of Euphorbia Factor L1,L2,L3,it may not be MRP2 and BCRP substrates;Euphorbia Factor L2 was uneasily absorbed in the intestine,its transmembrane transport process mainly passive transport with a concentration and time dependent,there is active transport,which suggested that Euphorbia Factor L2 may be a substrate for P-gp.However MRP2 and BCRP inhibitor have no effect on the Euphorbia Factor L2's transport,it may not be MRP2 and BCRP substrates;Euphorbia Factor L3 is uneasily absorbed in the intestine,its transmembrane transport of passive transport process-based,with a concentration and time dependent,there is active transport,which suggested that Euphorbia Factor L3 may be a substrate for P-gp.However MRP2 and BCRP inhibitor had no effect on transportation of Euphorbia Factor L3,may not be MRP2 and BCRP substrate;2,By the way of in vivo perfusion model to study Euphorbia Factor L1,L2,L3 absorption in the intestine,the results shows that Euphorbia Factor L1,L2,L3 absorption in the intestine for absorption medium,after added the P-gp inhibitor verapamil hydrochloride,Euphorbia Factor L1,L2 transfer coefficient Papp value increased significantly,indicating that this two compounds may be the substrate of P-gp.The MRP2 inhibitor had no significant effect on the Euphorbia Factor L1,L2,L3 transportation.3,Through the intestinal microsomal incubation in vitro experiments,the results shows that Euphorbia Factor L1,L2,L3 can be metabolized by intestinal microsomal enzyme,and may be CYP450 enzyme substrate.Conclusion:The Euphorbia Factor L1,L2,L3 may be P-gp substrate,by blocking the effect of P-gp efflux of substrates,the drugs increased the transmembrane transportation in the intestine,and increasing bioavailability.and can be metabolized by intestinal microsomal enzyme.Euphorbia Factor L1,L2,L3 by interfering with P-gp efflux function and activity of microsomal enzymes of drug in intestinal absorption in the intestine and even lead to toxicity,provided new ideas and methods for researching in intestinal drug toxicity.