The role of phosphate on Omniscan(®) dechelation: an in vitro relaxivity study at pH 7

Nephrogenic systemic fibrosis (NSF), a disease occurring in patients with severe renal failure, may be linked to injections of gadolinium chelates, contrast agents used for magnetic resonance imaging. A hypothesis frequently proposed to explain NSF is dissociation of Gd(3+) from its chelate, possibly from a deep storage compartment. Numerous in vivo and in vitro studies have been performed in an attempt to determine the extent of this dechelation and to understand its mechanism. Proton-assisted dechelation and transmetallation are the most widely described mechanisms of dechelation. This study investigated the possible ligand exchange role played by phosphate in the dechelation mechanism. Omniscan(®) dechelation was monitored in vitro by relaxivity measurements performed at physiological pH with different concentrations of phosphate buffer and in the presence of endogenous cations. Dechelation experiments performed on phosphate buffer alone showed that phosphate may induce gadolinium release by ligand exchange when the phosphate concentration in the buffer is higher than 130 mM for an Omniscan(®) concentration of 1.25 mM. This corresponds to a Gd/phosphate ratio of 10(-2). This ratio could be reached in vivo, especially in deep compartments such as bone. The presence of endogenous cations (Zn(2+), Cu(2+) or Ca(2+)) has also been demonstrated to accelerate the kinetics of gadolinium release, either by catalysing ligand exchange or by inducing a transmetallation mechanism. The Omniscan(®) formulation was also tested and the added Ca-DTPA-BMA was shown to increase dechelation kinetics in these experiments. This striking result may question the value of the Omniscan(®) formulation in the context of NSF.