Gadolinium‐containing magnetic resonance contrast media: investigation on the possible transchelation of Gd³⁺ to the glycosaminoglycan heparin

Abstract

Retention of gadolinium (Gd) in biological tissues is considered an important cofactor in the development of nephrogenic systemic fibrosis (NSF). Research on this issue has so far focused on the stability of Gd-based contrast media (GdCM) and a possible release of Gd³⁺ from the complex. No studies have investigated competing chelators that may occur in vivo. We performed proton T(1) -relaxometry in solutions of nine approved GdCM and the macromolecular chelator heparin (250 000 IU per 10 ml) without and with addition of ZnCl₂. For the three linear, nonspecific GdCM complexes, Omniscan®, OptiMARK® and Magnevist®, 2 h of incubation in heparin at 37 °C in the presence of 2.0 mm ZnCl₂ led to an increase in T₁-relaxivity by a factor of 7.7, 5.6 and 5.1, respectively. For the three macrocyclic complexes, Gadovist®, Dotarem® and Prohance®, only a minor increase in T₁-relaxivity by a factor of 1.5, 1.6 and 1.7 was found, respectively. Without addition of ZnCl₂, no difference between the two GdCM groups was observed (factors of 1.4, 1.2, 1.1, 1.3, 1.5 and 1.4, respectively). The increase in T₁-relaxivities observed for linear GdCM complexes may be attributable to partial transchelation with formation of a macromolecular Gd-heparin complex. For comparison, mixing of GdCl₃ and heparin results in a 8.7-fold higher T₁-relaxivity compared with a solution of GdCl₃ in water. Heparin is a glycosaminoglycan (GAG) and as such occurs in the human body as a component of the extracellular matrix. GAGs generally are known to be strong chelators. Gd³⁺ released from chelates of GdCM might be complexed by GAGs in vivo, which would explain their retention in biological tissues. Plasma GAG levels are elevated in end-stage renal disease; hence, our results might contribute to the elucidation of NSF.

Histology and Gadolinium Distribution in the Rodent Brain After the Administration of Cumulative High Doses of Linear and Macrocyclic Gadolinium-Based Contrast Agents

“…Two hypotheses for the increased signal intensity in the brain have been discussed in the literature: the recirculation from “reservoirs” (such as bone) 38,39 and the progressive alteration of the Gd chelate, from a low-relaxivity (eg, intact GBCA) to a high-relaxivity molecule (eg, Gd bound to a macromolecule). 40 As the high Gd concentrations in the skin and bone of animals administered with gadodiamide did not increase the levels of Gd in the brain compared with gadopentetate dimeglumine, a potential recirculation from “reservoirs” seems unlikely. However, the finding that the highest Gd concentrations in the deep cerebellar nuclei were measured up to 4 mg of Gd/kg (25.4 μmol Gd/kg tissue) supports the second hypothesis because a robust contrast enhancement requires a GBCA concentration of approximately 125 μmol Gd/L 41 and Wedeking et al 42 evaluated 30 μmol Gd/L as the MRI detection limit.…”

“…47 Gd ions derived from partial dissociation of GBCAs would not exist in free form in any significant amounts in the physiological environment, because of the presence of a multitude of high affinity binding partners, such as proteins, peptides, or inorganic phosphate or carbonate with very low solubility. The potential macromolecular binding partner and the Gd species responsible for the high MR signal intensity have not yet been identified, but potential binding partners are glucosaminoglycanes, 40 transferrin, 49 or parvalbumin. 50 Further studies are required to clarify how and to what extent transmetallation of the Gd from the intact GBCA to other binding partners/ligands might occur.…”

Quantification and Assessment of the Chemical Form of Residual Gadolinium in the Brain After Repeated Administration of Gadolinium-Based Contrast Agents

“…However, it is very unlikely that the intact GBCAs were bound to a macromolecule as their binding to plasma proteins is very low or negligible (Table 1). Several structural classes have been suggested as potential hosts for the Gd 3+ ion such as Ca 2+ -binding proteins, 42–46 which constitute one of the largest class of metalloproteins present in the extracellular and intracellular space, glucosaminoglycans, 47 apotransferrin, 48 or neuromelanins. 49 Some of them are relatively small macromolecules such as parvalbumin or calmodulin with molecular sizes of about 10 to 20 kDa, whereas others have sizes of several hundred kilodaltons or may be an integral part of the cell membrane.…”

Magnetic Resonance Imaging of Sacroiliitis in Patients with Spondyloarthritis: Correlation with Anatomy and Histology

“…As a result, there is greater affinity of gadolinium complexes from paramagnetic contrast agents, which also possess a negative charge, to the extracellular matrix of fibrocartilage [33]. This is the mechanism underlying late enhancement in damaged joints [34,35].…”