Speciation of Gd-based MRI contrast agents and potential products of transmetalation with iron ions or parenteral iron supplements.

The risk of transmetalation reactions between gadolinium complexes used as contrast agents for magnetic resonance imaging (MRI) and iron ions is examined under physiological conditions. A fast separation of gadopentetate (Gd-DTPA) and gadoterate (Gd-DOTA) and the respective Fe transmetalation products was accomplished by high-performance liquid chromatography. For detection, the LC system was coupled to an Orbitrap electrospray ionization mass spectrometer to achieve a detection limit as low as 50 nmol/L for Fe-DTPA. In vitro experiments revealed the formation of Fe-DTPA in blood plasma samples with Gd-DTPA and Fe(III) citrate. Analysis after different incubation times of the sample showed that the exchange of the metal ions is significantly dependent on time. If this reaction takes place in the body of MRI patients, this could explain why the disease nephrogenic systemic fibrosis (NSF) develops only after a longer retention of the linear Gd complex in the patient's body. Transmetalation either with endogenous Fe(II)/Fe(III) ions or with parenteral Fe supplements with Gd-DTPA could not be proven under the applied conditions. The high stability of Gd-DOTA is responsible that transmetalation between this macrocylic complex and neither of the Fe species was observed. These findings are important because NSF only develops after administration of Gd complexes with linear ligands. The results indicate that transmetalation reactions may be a trigger for the development of NSF, if free Fe(III) ions are accessible during a prolonged dwell time of Gd complexes with linear ligands in the patient's body.