Gadoxetate (Gd-EOB-DTPA) is a paramagnetic contrast agent developed for tissue contrast enhancement in hepatobiliary magnetic resonance imaging (MRI) (1-3).
Conventional paramagnetic contrast agents are generally metal chelates with unpaired electrons, and they work by shortening both the t1 and t2 relaxation times of surrounding water protons to produce a signal-enhancing effect (4, 5). At normal clinical doses of 0.1−0.2 mmol/kg, the t1 effect tends to dominate. Current agents are water-soluble compounds that distribute in the extracellular fluid and do not cross the intact blood−brain barrier (BBB). They are often used to enhance signals of central nervous system tissues that lack a BBB (e.g., pituitary gland), extraaxial tumors (e.g., meningiomas), and areas of BBB breakdown (e.g., tumor margins). These contrast agents can also be used in a similar nontargeted manner to enhance contrast between pathologies and surrounding normal areas in other organs (4-6).
Gadolinium(III) (Gd3+), a lanthanide metal ion with seven unpaired electrons, has been shown to be very effective at enhancing proton relaxation because of its high magnetic moment and very labile water coordination (5, 7-9). Gadopentetate dimeglumine (Gd-DTPA) was the first intravenous MRI contrast agent used clinically, and a number of similar Gd chelates or Gd-based contrast agents (GBCAs) have since been developed in an effort to further improve clinical efficacy, patient safety, and patient tolerance. The major chemical differences among these Gd chelates are the presence or absence of overall charge, ionic or nonionic, and their ligand frameworks (linear or macrocyclic). They are all non-targeted MRI contrast agents that are used in clinical practice.
Introduction of the lipophilic moiety, ethoxybenzyl, into the Gd chelate Gd-DTPA yielded Gd-EOB-DTPA (1). On i.v. administration, Gd-EOB-DTPA is taken up by both the liver and kidney and excreted into the urine and bile (10, 11). The uptake of Gd-EOB-DTPA by the hepatocytes allows differentiation between the healthy tissue and liver tumor because the tumorous liver tissue accumulates little Gd-EOB-DTPA (10, 12). This specific uptake mechanism is not entirely known because of evidence that the human organic anionic-transporter protein (OATP) is not involved (13). Excretion of Gd-EOB-DTPA in the bile may also permit visualization of both the gall bladder and the bile ducts. Gd-EOB-DTPA is highly soluble in water and exhibits low protein binding. Gd-EOB-DTPA is not commercially available in the United States, but it was approved as a MRI liver contrast agent in Sweden (3). In this formulation (0.25-mmol/ml injection), Gd-EOB-DTPA has an osmolality of 688 mOsm/kg H20 (at 37 ºC), viscosity of 1.19 mPa.s (at 37 ºC), and pH 7.0 (14).
Both renal and extra-renal toxicities have been reported following the clinical use of gadolinium in patients with underlying kidney disease (15-17). In 2007, the