title: Effect of common polymorphisms of the farnesoid X receptor and bile acid transporters on the pharmacokinetics of ursodeoxycholic acid.
abstract: Ursodeoxycholic acid (UDCA), a natural, dihydroxy bile acid, promotes gallstone dissolution and has been attributed with several other beneficial effects. The farnesoid X receptor (FXR) may influence the pharmacokinetics of UDCA by modulating the expression of bile acid transporters. This exploratory study examined whether common functional polymorphisms in FXR and in bile acid transporter genes affect the pharmacokinetics of exogenous UDCA. Polymorphisms in genes for transporters involved in bile acid transport, solute carrier organic anion 1B1 (SLCO1B1) 388A>G and 521T>C, solute carrier 10A1 (SLC10A1) 800 C>T and ATP-binding cassette B11 (ABCB11) 1331T>C, and the FXR -1G>T polymorphism were genotyped in 26 male Chinese subjects who ingested single oral 500-mg doses of UDCA. Plasma concentrations of UDCA and its major conjugate metabolite glycoursodeoxycholic acid (GUDCA) were determined. The mean systemic exposure of UDCA was higher in the five subjects with one copy of the FXR -1G>T variant allele than in those homozygous for the wild-type allele (n = 21) (AUC0-24 h : 38.5 ± 28.2 vs. 20.9 ± 8.0 μg h/mL, P = 0.021), but this difference appeared mainly due to one outlier with the -1GT genotype and elevated baseline and post-treatment UDCA concentrations. After excluding the outlier, body weight was the only factor associated with plasma concentrations of UDCA and there were no significant associations with the other polymorphisms examined. None of the polymorphisms affected the pharmacokinetics of GUDCA. This study showed that the common polymorphisms in bile acid transporters had no significant effect on the pharmacokinetics of exogenous UDCA but an effect of the FXR polymorphism cannot be excluded.
authors.affiliation: Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Miao
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Benny S P
authors.initials: BS
authors.lastname: Fok
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Siu-Kwan
authors.initials: SK
authors.lastname: Wo
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Vincent H L
authors.initials: VH
authors.lastname: Lee
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zuo
authors.affiliation: Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Brian
authors.initials: B
authors.lastname: Tomlinson
mesh_terms: D000328:Adult; D001647:Bile Acids and Salts / Q000378:metabolism*; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D014580:Ursodeoxycholic Acid / Q000493:pharmacokinetics*; D055815:Young Adult; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D026901:Membrane Transport Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014580:Ursodeoxycholic Acid; D000099150:Receptor, Farnesoid X-Activated
keywords: farnesoid X receptor; pharmacogenetics; pharmacokinetics; ursodeoxycholic acid