title: Decreased liver distribution of entecavir is related to down-regulation of Oat2/Oct1 and up-regulation of Mrp1/2/3/5 in rat liver fibrosis.
abstract: OBJECTIVE
  We aimed to elucidate whether entecavir was taken-up into liver by transporters and clarify the possible molecular mechanisms of changes in the distribution of entecavir in rat liver fibrosis.
  
  
  METHODS
  Thioacetamide (TAA) was applied to induce rat liver fibrosis. Samples of liver uptake index (LUI) study and uptake of entecavir in isolated rat hepatocytes were determined by LC-MS/MS. qRT-PCR and western blotting were used to examine the expression of transporters in rat liver.
  
  
  RESULTS
  The uptake of entecavir in hepatocytes was significantly higher at 37 °C compared to 4 °C. Furthermore, TEA and PAH could inhibit significantly the uptake of entecavir by the hepatocytes. It indicated that Oat2 and Oct1 were contributed to uptake of entecavir. Compared with control group, LUI and the uptake of entecavir, PAH and TEA in hepatocytes were significantly reduced in liver fibrosis group. Further study indicated that entecavir Vmax in liver fibrosis group was significantly decreased while the Km was not changed. These results indicated that transport capacity TAA treated isolated rat liver hepatocytes were reduced. Oat2 and Oct1 expressions were down-regulated and Mrp1/2/3/5 mRNA expressions were up-regulated in liver fibrosis group.
  
  
  CONCLUSIONS
  The changes of these transporters were contributed to decrease liver distribution of entecavir.
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China.
authors.forename: Qinghan
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China.
authors.forename: Changyuan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Meng
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China.
authors.forename: Huijun
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China.
authors.forename: Jinyong
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China.
authors.forename: Pengyuan
authors.initials: P
authors.lastname: Sun
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Huo
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China. Electronic address: kexinliu@dlmedu.edu.cn.
authors.forename: Kexin
authors.initials: K
authors.lastname: Liu
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000097:blood; D050482:Catecholamine Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D005355:Fibrosis; D006147:Guanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D013853:Thioacetamide; D015854:Up-Regulation
chemical_list: D000410:Alanine Transaminase; D000998:Antiviral Agents; D001219:Aspartate Aminotransferases; D050482:Catecholamine Plasma Membrane Transport Proteins; D006147:Guanine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D029362:Organic Anion Transporters, Sodium-Independent; D012333:RNA, Messenger; D013853:Thioacetamide; C493212:Slc22a1 protein, rat; C088800:Slc22a7 protein, rat; C413685:entecavir
keywords: Entecavir; Liver fibrosis; Transporter