Gadobutrol (Gd-DO3A-butrol) is a nonionic, paramagnetic contrast agent developed for tissue contrast enhancement in magnetic resonance imaging (MRI) (1-3).
Water-soluble 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 the signal-enhancing effect (1, 2, 4). 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 (CNS) tissues that lack a BBB (e.g., pituitary gland), extraaxial tumors (e.g., meningiomas), and areas of BBB breakdown (e.g., tumor margins). In these cases, small or multiple CNS lesions are more clearly delineated with contrast enhancement. In addition, contrast enhancement can highlight vasculature, delineate the extent of disease, and confirm the impression of normal or nonmalignant tissues. These contrast agents can also be used in a similar nonspecific manner to enhance contrast between pathologies and surrounding normal areas in other organs (1, 2, 5).
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 (2, 6-9). Gadopentetate dimeglumine (Gd-DTPA) was the first intravenous MRI contrast agent used clinically, and a number of similar Gd chelates have been developed in an effort to further improve clinical efficacy, patient safety and patient tolerance. The major chemical differences among these Gd chelates or Gd-based contrast agents (GBCAs) are the presence or absence of overall charge, ionic or nonionic, and their ligand frameworks (linear or macrocyclic). Gd-DO3A-butrol has a macrocyclic framework and is neutral (10, 11). The DO3A-butrol ligand was developed based on the belief that high overall hydrophilicity of an agent is generally associated with very low protein binding and good biological tolerance (12). It is a modification of the Gd-DO3A compound in which a trihydroxybutyl group is attached to the macrocyclic ligand to ensure high hydrophilicity. The ligand contains two chiral carbons at C-13 and C-14, therefore, the product is a racemic mixture of (13R, 14S)− and (13S, 14R)−. The Gd(III) in Gd-DO3A-butrol has a coordination number of 9. Gd-DO3A-butrol is a water-soluble, highly hydrophilic compound with a partition coefficient between n-butanol and buffer at pH 7.6 of ~ 0.006 (13).
Gd-DO3A-butrol is not commercially available in the United States, but it is commercially available in Canada at a concentration of 1.0 mmol/ml (604.72 mg/ml) for contrast enhancement during cranial and spinal imaging with MRI and MR angiography. At this concentration, it has an osmolarity of 1117 mOsm/kg at 37 ºC, viscosity of 4.96 mPa at 37 ºC, and log P(n-octanol/water) of −5.4 at 25 ºC.
Both renal and extra-renal toxicities have been reported following the clinical use of gadolinium in patients with underlying kidney disease (14-16). In 2007, the