RT Journal Article
SR Electronic
T1 Hepatic Uptake of the Magnetic Resonance Imaging Contrast Agent Gd-EOB-DTPA: Role of Human Organic Anion Transporters
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1024
OP 1028
DO 10.1124/dmd.110.032862
VO 38
IS 7
A1 Leonhardt, Mirko
A1 Keiser, Markus
A1 Oswald, Stefan
A1 Kühn, Jens
A1 Jia, Jia
A1 Grube, Markus
A1 Kroemer, Heyo K.
A1 Siegmund, Werner
A1 Weitschies, Werner
YR 2010
UL http://dmd.aspetjournals.org/content/38/7/1024.abstract
AB 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 (IC50 = 0.6 mM) and OATP1B3 (IC50 = 0.4 mM). In comparison, the IC50 values for rifampicin were 11.9 (OATP1B1), 1.4 (OATP1B3), and 80.5 μM (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 (Km = 0.7 mM, Vmax = 10.5 pmol/mg × min), OATP1B3 (Km = 4.1 mM, Vmax = 22.7 pmol/mg × min), and NTCP (Km = 0.04 mM, Vmax = 1.4 pmol/mg × 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. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics