title: Effect of cholecystectomy on bile acids as well as relevant enzymes and transporters in mice: Implication for pharmacokinetic changes of rifampicin.
abstract: OBJECTIVE
  Long-term medical consequences of cholecystectomy are believed to be uncommon. It has been reported that bile acids (BAs) changed after cholecystectomy. As important signaling molecules, the alternations of BAs might favour the regulatory effect on enzymes and transporters involved in BAs physiological homeostasis at the transcriptional level, which could lead to pharmacokinetic changes of drugs. Here, we determined the effect of cholecystectomy on BAs, relevant enzymes and transporters and pharmacokinetic parameters of rifampicin, and explored the potential mechanisms at the transcriptional regulatory level via nuclear receptors.
  
  
  METHODS
  Parameters of BAs in different specimens, mRNA and protein expression of enzymes, transporters and nuclear receptors that relate to BAs homeostasis in liver and ileum, and the pharmacokinetic character of rifampicin were measured in sham-operated and cholecystectomized mice.
  
  
  RESULTS
  Cholecystectomy associated with considerable decreased BAs pool size that could attribute to increased fecal excretion. Most notably, as the Fxr and Pxr ligands, the alternations of hepatic and ileal individual BAs affected expression of enzymes Cyp3a11 and transporters Ntcp and Bsep in liver and Asbt in ileum significantly following cholecystectomy. Eventually, the rifampicin bioavailability was improved with depressed clearance in mice without gallbladders.
  
  
  CONCLUSIONS
  As natural ligands for Fxr and Pxr, the alternations of individual BAs lead to the regulation of hepatic and ileal relevant enzymes and transporters after cholecystectomy. Especially, the down-regulation of hepatic Cyp3a11 suggests that undesirable pharmacokinetic alternations of drugs especially Cyp3a11 substrates like rifampicin might occur in phase with cholecystectomy.
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou, China; Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Qin
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou, China; Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, China.
authors.forename: Yanshu
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, China.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Xi
authors.affiliation: Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Rao
authors.affiliation: Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, China.
authors.forename: Yanrong
authors.initials: Y
authors.lastname: Ma
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou, China; Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, China.
authors.forename: Yingting
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, China. Electronic address: xinanwu6511@126.com.
authors.forename: Xinan
authors.initials: X
authors.lastname: Wu
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D000904:Antibiotics, Antitubercular / Q000493:pharmacokinetics*; D001647:Bile Acids and Salts / Q000097:blood / Q000378:metabolism*; D002763:Cholecystectomy; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D007082:Ileum / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D012293:Rifampin / Q000493:pharmacokinetics*; D027981:Symporters / Q000235:genetics; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D000904:Antibiotics, Antitubercular; D001647:Bile Acids and Salts; D051544:Cytochrome P-450 CYP3A; D008565:Membrane Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D012293:Rifampin; D027981:Symporters; D000099150:Receptor, Farnesoid X-Activated; C490549:Abcb11 protein, mouse; C071908:sodium-bile acid cotransporter; C496508:Cyp3a11 protein, mouse
keywords: Bile acids; Cholecystectomy; Enzymes; Nuclear reporters; Pharmacokinetics; Transporters