title: Combined rifampicin and ursodeoxycholic acid treatment does not amplify rifampicin effects on hepatic detoxification and transport systems in humans.
abstract: BACKGROUND
  Rifampicin (RIFA) and ursodeoxycholic acid (UDCA) were found to stimulate different but complementary hepatobiliary detoxification pathways in gallstone patients.
  
  
  OBJECTIVE
  To study whether single drug effects are sustained or even enhanced by combination of both drugs and whether possible effects are mediated by circulating fibroblast growth factor 19 (FGF19), which has recently been identified as a master regulator of bile acid biosynthesis.
  
  
  METHODS
  20 patients scheduled for laparoscopic cholecystectomy were randomized to a combination of UDCA (1 g/day during 3 weeks before surgery) and RIFA (600 mg/day during 1 week before surgery), or no treatment. Routine biochemistry, lipids, bile acid synthesis (7α-hydroxy-4-cholesten-3-one, C-4) and FGF19 were measured in serum. Bile acids were analyzed in serum and bile. A wedge liver biopsy was taken for determination of expression of hepatobiliary ABC transporters on mRNA and protein levels and of enzymes and regulatory transcription factors involved in the metabolism of biliary compounds on mRNA levels.
  
  
  RESULTS
  Combination treatment with both RIFA and UDCA significantly stimulated bile acid and bilirubin detoxification (CYP3A4, p < 0.001), conjugation (UGT1A1, p < 0.001) and elimination (MRP2, p < 0.05), as well as bile acid synthesis (p < 0.05), as compared to untreated controls. Notably, serum FGF19 levels in RIFA- and UDCA-treated patients did not differ from controls.
  
  
  CONCLUSIONS
  Combined treatment with RIFA and UDCA preserves the previously observed beneficial effects of single treatment with RIFA, including stimulation of bile acid synthesis. Most notably, the latter effect in humans is not mediated by FGF19.
authors.affiliation: Department of Internal Medicine, The Sahlgrenska Academy, Institute of Medicine, Gothenburg, Sweden. hanns-ulrich.marschall@gu.se
authors.forename: Hanns-Ulrich
authors.initials: HU
authors.lastname: Marschall
authors.forename: Martin
authors.initials: M
authors.lastname: Wagner
authors.forename: Gernot
authors.initials: G
authors.lastname: Zollner
authors.forename: Peter
authors.initials: P
authors.lastname: Fickert
authors.forename: Dagmar
authors.initials: D
authors.lastname: Silbert
authors.forename: Ulf
authors.initials: U
authors.lastname: Gustafsson
authors.forename: Staffan
authors.initials: S
authors.lastname: Sahlin
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
mesh_terms: D000328:Adult; D000368:Aged; D001646:Bile / Q000737:chemistry; D001647:Bile Acids and Salts / Q000032:analysis / Q000096:biosynthesis; D001692:Biological Transport / Q000187:drug effects; D001706:Biopsy; D002756:Cholagogues and Choleretics / Q000008:administration & dosage / Q000493:pharmacokinetics; D002769:Cholelithiasis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008658:Inactivation, Metabolic; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D004791:Enzyme Inhibitors; D014580:Ursodeoxycholic Acid; D012293:Rifampin