title: No significant effect of the SLCO1B1 polymorphism on the pharmacokinetics of ursodeoxycholic acid.
abstract: OBJECTIVE
  To investigate possible effects of the SLCO1B1 polymorphism on the pharmacokinetics of ursodeoxycholic acid (UDCA) and its metabolites in healthy volunteers.
  
  
  METHODS
  In a crossover study with two phases, 15 healthy volunteers with the SLCO1B1*1A/*1A genotype, seven with the *1B/*1B genotype, and five with the *15/*15 or *5/*15 genotype ingested placebo or a single 150-mg dose of UDCA. Plasma concentrations of bile acids and their biosynthesis marker were determined up to 24 h post-ingestion by liquid chromatography-tandem mass spectrometry.
  
  
  RESULTS
  The SLCO1B1 genotype had no significant effect on the pharmacokinetics of UDCA. The geometric mean ratios (95% confidence interval) of UDCA area under the plasma concentration-time curve from 0 to 12 h (AUC(0-12)) in subjects with the SLCO1B1*1B/*1B genotype and in subjects with the SLCO1B1*15/*15 or *5/*15 genotype to the AUC(0-12) in subjects with the SLCO1B1*1A/*1A genotype were 1.07 (0.85, 1.35; P = 0.459) and 0.93 (0.75, 1.15; P = 0.563), respectively. In addition, following either placebo or UDCA administration, the SLCO1B1 polymorphism showed no association with the AUC(0-24) of the glycine and taurine conjugates of UDCA, with endogenous bile acids, or with the incremental AUC(0-24) of a bile acid synthesis marker. Compared with placebo, UDCA ingestion increased the AUC(0-24) of cholic acid, glycochenodeoxycholic acid, glycocholic acid, and glycodeoxycholic acid by 1.5-, 1.1-, 1.2-, and 1.2- fold (P < 0.05), respectively.
  
  
  CONCLUSIONS
  Genetic polymorphism in SLCO1B1 does not affect pharmacokinetics of UDCA, suggesting that OATP1B1 is not rate-limiting to the hepatic uptake of therapeutic UDCA. Further studies are required to clarify the mechanisms by which UDCA increases the plasma concentrations of endogenous bile acids.
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, PO Box 705, 00029 HUS, Helsinki, Finland.
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Xiang
authors.forename: Juha
authors.initials: J
authors.lastname: Vakkilainen
authors.forename: Janne T
authors.initials: JT
authors.lastname: Backman
authors.forename: Pertti J
authors.initials: PJ
authors.lastname: Neuvonen
authors.forename: Mikko
authors.initials: M
authors.lastname: Niemi
mesh_terms: D001647:Bile Acids and Salts / Q000096:biosynthesis / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002756:Cholagogues and Choleretics / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D003627:Data Interpretation, Statistical; D005260:Female; D005838:Genotype; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D027361:Organic Anion Transporters / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D053719:Tandem Mass Spectrometry; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D001647:Bile Acids and Salts; D015415:Biomarkers; D002756:Cholagogues and Choleretics; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D014580:Ursodeoxycholic Acid