title: Hepatic uptake of the magnetic resonance imaging contrast agent Gd-EOB-DTPA: role of human organic anion transporters.
abstract: Contrast-enhancing magnetic resonance imaging with the liver-specific agent gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) has been shown to improve the detection rate of focal lesions. There is evidence from preclinical studies that multidrug organic anion transporters are involved in hepatic uptake of Gd-EOB-DTPA. Therefore, we evaluated affinity of the contrast agent to human organic anion-transporting polypeptides (OATP1B1, OATP1B3, OATP2B1) and to the Na(+)/taurocholate cotransporting polypeptide (NTCP) using stable transfected human embryonic kidney (HEK) 293 cells. In competition assays, Gd-EOB-DTPA inhibited the uptake of bromosulfophthalein (BSP) by OATP1B1 (IC(50) = 0.6 mM) and OATP1B3 (IC(50) = 0.4 mM). In comparison, the IC(50) values for rifampicin were 11.9 (OATP1B1), 1.4 (OATP1B3), and 80.5 muM (OATP2B1), respectively. Uptake of BSP by OATP2B1, uptake of taurocholic acid by NTCP, and viability of all HEK cells were not influenced by Gd-EOB-DTPA in concentrations up to 10 mM. In uptake assays using a new liquid chromatography-tandem mass spectrometry method for quantification, Gd-EOB-DTPA was a substrate for OATP1B1 (K(m) = 0.7 mM, V(max) = 10.5 pmol/mg x min), OATP1B3 (K(m) = 4.1 mM, V(max) = 22.7 pmol/mg x min), and NTCP (K(m) = 0.04 mM, V(max) = 1.4 pmol/mg x min). The uptake by OATP2B1 was not different from the vector control. In conclusion, Gd-EOB-DTPA is a substrate of the liver-specific OATP1B1, OATP1B3, and NTCP.
authors.affiliation: Department of Pharmacy, Ernst-Moritz-Arndt-University of Greifswald, Greifswald, Germany.
authors.forename: Mirko
authors.initials: M
authors.lastname: Leonhardt
authors.forename: Markus
authors.initials: M
authors.lastname: Keiser
authors.forename: Stefan
authors.initials: S
authors.lastname: Oswald
authors.forename: Jens
authors.initials: J
authors.lastname: Kühn
authors.forename: Jia
authors.initials: J
authors.lastname: Jia
authors.forename: Markus
authors.initials: M
authors.lastname: Grube
authors.forename: Heyo K
authors.initials: HK
authors.lastname: Kroemer
authors.forename: Werner
authors.initials: W
authors.lastname: Siegmund
authors.forename: Werner
authors.initials: W
authors.lastname: Weitschies
mesh_terms: D001667:Binding, Competitive; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003287:Contrast Media / Q000378:metabolism; D019786:Gadolinium DTPA / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008279:Magnetic Resonance Imaging / Q000379:methods; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism; D012293:Rifampin / Q000378:metabolism; D013379:Substrate Specificity; D013448:Sulfobromophthalein / Q000378:metabolism; D027981:Symporters / Q000378:metabolism; D013656:Taurocholic Acid / Q000378:metabolism
chemical_list: D003287:Contrast Media; D027361:Organic Anion Transporters; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; C073590:gadolinium ethoxybenzyl DTPA; D013448:Sulfobromophthalein; C071908:sodium-bile acid cotransporter; D013656:Taurocholic Acid; D019786:Gadolinium DTPA; D012293:Rifampin