title: Molecular mechanisms of biliary excretion of cefditoren and the effects of cefditoren on the expression levels of hepatic transporters.
abstract: Cefditoren, a third generation cephalosporin antibiotics, has been used in clinics extensively. Previous results have indicated that cefditoren is excreted into bile as unchanged form. To investigate whether canalicular membrane transporters of hepatocytes were involved in the biliary excretion of cefditoren, we examined the hepatobiliary disposition of cefditoren using probenecid, novobiocin and verapamil as inhibitors of Mrp2, Bcrp and P-gp respectively in perfused rat livers. The values for the hepatic extraction ratio had no statistical significance, whereas cumulative biliary excretion rates of cefditoren were significantly reduced to 43.8% and 79.5% over 25 min in the perfused probenecid and novobiocin rats, respectively. We further investigated the effects of cefditoren on the expression of hepatic transporters by RT-PCR and Western blot after oral administration of cefditoren one week. The expression levels of Mrp2, Bcrp, Oat2 mRNA were markedly increased, while P-gp and Oct1 mRNA were decreased. In concordance with RT-PCR results, Mrp2 expression level increased by Western blotting. These results indicate that Mrp2 and Bcrp may be involved in the biliary excretion of cefditoren. Cefditoren can up-regulate the expression levels of Mrp2, Bcrp and Oat2, and down-regulate P-gp and Oct1 mRNA expression. These results provide important data for drug-drug interactions.
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Meng
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.forename: Changyuan
authors.initials: C
authors.lastname: Wang
authors.forename: Huijun
authors.initials: H
authors.lastname: Sun
authors.forename: Taiichi
authors.initials: T
authors.lastname: Kaku
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kato
authors.forename: Kexin
authors.initials: K
authors.lastname: Liu
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D001646:Bile / Q000378:metabolism*; D002511:Cephalosporins / Q000493:pharmacokinetics* / Q000494:pharmacology; D004347:Drug Interactions; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009675:Novobiocin / Q000494:pharmacology; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics; D011339:Probenecid / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; C489249:Abcg2 protein, rat; D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D029362:Organic Anion Transporters, Sodium-Independent; D012333:RNA, Messenger; C088800:Slc22a7 protein, rat; D009675:Novobiocin; C073460:cefditoren; D014700:Verapamil; D011339:Probenecid