Department of Pharmacy, Ernst-Moritz-Arndt-University of Greifswald, Greifswald, Germany.
Drug Metab Dispos. 2010 Jul;38(7):1024-8. doi: 10.1124/dmd.110.032862. Epub 2010 Apr 20.
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.
钆塞酸二钠（Gd-EOB-DTPA）是一种肝脏特异性的造影剂，它的使用可以提高局灶性病变的检出率。临床前研究表明，多药有机阴离子转运体参与了 Gd-EOB-DTPA 的肝脏摄取过程。因此，我们使用稳定转染的人胚肾（HEK）293 细胞来评估该造影剂与人类有机阴离子转运蛋白（OATP1B1、OATP1B3、OATP2B1）和 Na+/牛磺胆酸钠共转运蛋白（NTCP）的亲和力。在竞争实验中，Gd-EOB-DTPA 抑制了 BSP 被 OATP1B1（IC50=0.6 mM）和 OATP1B3（IC50=0.4 mM）摄取。相比之下，利福平的 IC50 值分别为 11.9（OATP1B1）、1.4（OATP1B3）和 80.5 μM（OATP2B1）。在 10 mM 浓度范围内，Gd-EOB-DTPA 对 OATP2B1 摄取 BSP、NTCP 摄取牛磺胆酸钠以及所有 HEK 细胞的活力均无影响。在使用新的液相色谱-串联质谱法进行定量的摄取实验中，Gd-EOB-DTPA 是 OATP1B1（K m=0.7 mM，V max=10.5 pmol/mg·min）、OATP1B3（K m=4.1 mM，V max=22.7 pmol/mg·min）和 NTCP（K m=0.04 mM，V max=1.4 pmol/mg·min）的底物。OATP2B1 的摄取与载体对照没有区别。综上所述，Gd-EOB-DTPA 是肝脏特异性 OATP1B1、OATP1B3 和 NTCP 的底物。
