The Involvement Of Multidrug And Toxin Extrusion Protein 1 And Breast Cancer Resistance Protein In The Distribution And Excretion Of Berberine

Aim:Berberine(BBR),an isoquinoline alkaloid,has demonstrated multiple clinical pharmacological actions.As a substrate of multiple transporters in the liver,BBR is rarely excreted into the bile but can be found in the urine.The purpose of the present study was to investigate the role of the important transporters,Multidrug and toxin extrusion protein 1(MATE1)and Breast cancer resistance protein(BCRP),in the distribution and excretion of BBR.Methods: Using hMATE1-HEK293 cells and rat primary hepatocytes,we investigated the effect of MATE1/Mate1 on cellular uptake and efflux of BBR by changing pH or using PYR(MATE1 inhibitor).Then,the effect of PYR on distribution and excretion of intravenously injected BBR in rats was detected by in vivo assays.In addition,the effect of PYR on distribution of intravenously injected BBR in mouse livers and kidneys was investigated as well.The hBCRP-MDCK?cells were used to investigate the effect of KO143(BCRP inhibitor)on transport of BBR.In addition,we used Bcrp-KO mice to investigate the potential effect of Bcrp on tissue distribution and plasma exposure of oral administrated BBRResults: Using human MATE1(hMATE1)-transfected HEK293 cells,BBR was shown to be a substrate of hMATE1(Km=4.28±2.18 ?M).In primary rat hepatocytes,pH-dependent uptake and efflux studies suggested that the transport of BBR was driven by the exchange of H+ and involved Mate1.In rats,we found that pyrimethamine(PYR),an inhibitor of Mate1,increased hepatic and renal distribution of BBR and decreased urinary excretion of BBR.Results observed in mice were in accordance with those in rats.In hBCRP-MDCK?cells,KO143 had no significant effect on net efflux rate(Rnet)of BBR.In addition,there is no obvious difference between the distribution of BBR in Bcrp-KO mice and wide type mice.Conclusion: These findings indicated that BBR is a substrate of MATE1 but not BCRP,and that hepatic and renal Mate1 promote the excretion of BBR into bile and urine,respectively.In conclusion,Mate1 plays a key role in the distribution and excretion of BBR,and we speculate that drug-drug interactions(DDIs)caused by MATE1 may occur between BBR and other co-administered drugs.