title: Visualization of hepatic uptake transporter function in healthy subjects by using gadoxetic acid-enhanced MR imaging.
abstract: OBJECTIVE
  To determine if genetic polymorphisms of liver-specific human organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 influence cellular uptake of gadoxetic acid in vitro and if functionally relevant polymorphisms are confounders for liver enhancement by gadoxetic acid in healthy subjects.
  
  
  METHODS
  This study received ethics approval, and all subjects provided written informed consent. Cellular uptake of gadoxetic acid by OATP1B1 and OATP1B3 and their frequent genetic variants was measured by using stable transfected embryonic kidney HEK293 cells. Liver signal intensity at gadoxetic acid-enhanced MR imaging and pharmacokinetics of gadoxetic acid were evaluated in 36 healthy carriers of SLCO1B1/1B3 wild-type alleles (n = 10), SLCO1B1*1b/*1b (n = 8), SLCO1B1*15/*15 (n = 7), SLCO1B1*5/*15 (n = 1), SLCO1B1*1a/*5 (n = 6), and SLCO1B3*4/*4 (n = 4) by using T1-weighted MR imaging and liquid chromatography tandem mass spectrometry.
  
  
  RESULTS
  Transport activity for gadoxetic acid was increased in cells transfected with SLCO1B1c.388A>G (12.8 pmol/[mg·min]6 3.53, P = .001) but decreased in cells with SLCO1B1c.388A>G/521T>C (3.11 pmol/[mg·min] ± 0.918, P = .004) compared with cells with nonvariant transporter (6.32 pmol/[mg·min] ± 2.73). Compared with activity of cells transfected with the nonvariant SLCO1B3 (7.43 pmol/[mg·min] ± 2.43), SLCO1B3c.699G>A was a gain-of-function variant (15.1 pmol/[mg·min] ± 5.52, P = .002), whereas SLCO1B3c.334T>G (0.364 pmol/[mg·min] ± 0.125, P = .0001) and SLCO1B3c.1564G>T (0.295 pmol/[mg·min] ± 0.247, P = .0001) were variants with lower function. Liver enhancement with gadoxetic acid was reduced in subjects with OATP1B1*1a/*5 compared with wild-type subjects and those with OATP1B1*1b/*1b (area under enhancement curve, 3-480 minutes in arbitrary units [au]; 20.7 au ± 6.85 vs 36.5 au ± 8.08 [P = .006] vs 34.6 au ± 8.92 [P = .026]). The OATP1B3*4 polymorphism was not of functional relevance. No pharmacokinetic characteristics of gadoxetic acid were influenced by genetic polymorphisms of OATP1B1 and OATP1B3.
  
  
  CONCLUSIONS
  Liver-specific OATP1B1 and OATP1B3 are uptake carriers for gadoxetic acid in subjects. Genetic polymorphisms of OATP1B1 are signal confounders in gadoxetic acid-enhanced liver MR imaging.
authors: Department of Clinical Pharmacology, Ernst-Moritz-Arndt University Greifswald, Ferdinand-Sauerbruch-Strasse NK, Greifswald D-17475, Germany.
authors: Ali
authors: A
authors: Nassif
authors: Jia
authors: J
authors: Jia
authors: Markus
authors: M
authors: Keiser
authors: Stefan
authors: S
authors: Oswald
authors: Christiane
authors: C
authors: Modess
authors: Stefan
authors: S
authors: Nagel
authors: Werner
authors: W
authors: Weitschies
authors: Norbert
authors: N
authors: Hosten
authors: Werner
authors: W
authors: Siegmund
authors: Jens-Peter
authors: JP
authors: Kühn
mesh_terms: D000483:Alleles; D000704:Analysis of Variance; D019540:Area Under Curve; D015153:Blotting, Western; D002853:Chromatography, Liquid; D003287:Contrast Media / Q000493:pharmacokinetics*; D019786:Gadolinium DTPA / Q000493:pharmacokinetics*; D005838:Genotype; D006801:Humans; D008099:Liver / Q000166:cytology* / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1; D008279:Magnetic Resonance Imaging / Q000379:methods*; D027361:Organic Anion Transporters / Q000235:genetics*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D053719:Tandem Mass Spectrometry; D014162:Transfection
chemical_list: D003287:Contrast Media; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; C073590:gadolinium ethoxybenzyl DTPA; D019786:Gadolinium DTPA