The effects of multidrug resistance protein 2 (Mrp2) and breast cancer resistance protein (Bcrp) on biliary excretion of cefditoren in rats

Objective Cefditoren,a third-generation cephalosporin antibiotics,has been used in clinic extensively.Whether Mrp2 or other canalicular transporters such as Bcrp and P-gp are involved in the biliary excretion of cefditoren is unknown.This study is performed to investigate the role of the canalicular transporters in the biliary excretion of cefditoren and the effect of cefditoren on expression levels of some hepatic transporters.Methods We examined the hepatobiliary disposition of cefditoren using probenecid,novobiocin and verapamil as the inhibitors of Mrp2,Bcrp and P-gp respectively in perfused rat livers.The concentration of cefditoren in the perfusate and bile were determined by RP-HPLC with ultraviolet detection at 295nm using a mobile phase composed of 0.1% ammonium acetate-methanol(65∶35).We also investigated the effects of cefditoren on expression of hepatic transporters.The change in mRNA of main canalicular transporters was investigated by RT-PCR and Western blot after administration of cefditoren.Results The values for the hepatic extraction ratio did not change,whereas cumulative biliary excretion rates of cefditoren were significantly reduced to 43.78% and 79.52% over 25 min in the perfused probenecid and novobiocin rats,respectively.After oral administration of cefditoren,the expression levels of Mrp2,Bcrp,Oat2 mRNA were markedly up-regulated,while Mdr1a and Oct1 mRNA were down-regulated by RT-PCR.In concordance with RT-PCR results,Mrp2 expression level was up-regulated by Western blot.Conclusions Mrp2 and Bcrp mediated the biliary excretion of cefditoren,whereas P-gp had no contribution to the transportation of cefditoren into bile.The expression levels of Mrp2,Bcrp and Oat2 mRNA were up-regulated and the expression levels of Mdr1a and Oct1 mRNA were down-regulated by cefditoren.These results provide important data for drug-drug interaction.