title: Transporters involved in the hepatic uptake of (99m)Tc-mebrofenin and indocyanine green.
abstract: OBJECTIVE
  (99m)Tc-mebrofenin hepatobiliary scintigraphy (HBS) and the indocyanine green (ICG) clearance test are used for the assessment of hepatic function before and after liver surgery. The hepatic uptake of (99m)Tc-mebrofenin and ICG is considered similar to the uptake of organic anions such as bilirubin and bile acids. Little is known about hepatic uptake mechanisms of both compounds and recent evidence suggests that the hepatic transporters for ICG and (99m)Tc-mebrofenin are distinct. The aim of this study was to identify the specific human hepatic transporters of (99m)Tc-mebrofenin and ICG.
  
  
  METHODS
  The uptake of (99m)Tc-mebrofenin was investigated in cRNA-injected Xenopus laevis oocytes expressing human OATP1B1, OATP1B3, OATP2B1, or NTCP. Chinese hamster ovary (CHO) cells stably expressing OATP1B1, OATP1B3, OATP2B1, or NTCP were used as a mammalian expression system. ICG transport into CHO cells was additionally imaged with confocal microscopy.
  
  
  RESULTS
  We demonstrated that OATP1B1 and OATP1B3 are involved in the transport of (99m)Tc-mebrofenin. OATP1B1 showed an approximately 1.5-fold higher affinity for (99m)Tc-mebrofenin compared to OATP1B3. ICG is transported by OATP1B3 and NTCP.
  
  
  CONCLUSIONS
  The transporter specificity of (99m)Tc-mebrofenin and ICG partially overlaps as both compounds are transported by OATP1B3. (99m)Tc-mebrofenin is also taken up by OATP1B1, whereas ICG is additionally transported by NTCP.
authors.affiliation: Department of Experimental Surgery, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Wilmar
authors.initials: W
authors.lastname: de Graaf
authors.forename: Stephanie
authors.initials: S
authors.lastname: Häusler
authors.forename: Michal
authors.initials: M
authors.lastname: Heger
authors.forename: Tessa M
authors.initials: TM
authors.lastname: van Ginhoven
authors.forename: Gert
authors.initials: G
authors.lastname: van Cappellen
authors.forename: Roelof J
authors.initials: RJ
authors.lastname: Bennink
authors.forename: Gerd A
authors.initials: GA
authors.lastname: Kullak-Ublick
authors.forename: Rolf
authors.initials: R
authors.lastname: Hesselmann
authors.forename: Thomas M
authors.initials: TM
authors.lastname: van Gulik
authors.forename: Bruno
authors.initials: B
authors.lastname: Stieger
mesh_terms: D000814:Aniline Compounds; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D005998:Glycine; D006801:Humans; D007098:Imino Acids / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007208:Indocyanine Green / Q000493:pharmacokinetics*; D008099:Liver / Q000000981:diagnostic imaging / Q000378:metabolism; D008111:Liver Function Tests; D027381:Liver-Specific Organic Anion Transporter 1; D018613:Microscopy, Confocal; D009865:Oocytes / Q000378:metabolism; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D015609:Organotechnetium Compounds / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014982:Xenopus laevis
chemical_list: D000814:Aniline Compounds; D007098:Imino Acids; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; D011994:Recombinant Proteins; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; C450859:SLCO2B1 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D027981:Symporters; C071908:sodium-bile acid cotransporter; C034837:technetium Tc 99m mebrofenin; D007208:Indocyanine Green; D005998:Glycine