Gadolinium Contrast Agents

Because of the toxicity of free gadolinium (Gd³⁺), MRI contrast agents contain gadolinium bound to chelates. The stability of the gadolinium ion in the agent is, therefore, an important factor in its safety profile. Factors that can affect stability are the shape (linear vs. cyclic) and ionicity (ionic vs. non-ionic) of the chelate.

The nine gadolinium contrast agents currently available for clinical use can be classified as ionic or non-ionic and linear or cyclic. Ionic agents have negatively charged groups that tend to offer better binding of the positively charged gadolinium ion compared to the non-ionic agents.

Cyclic agents are constructed so as to encircle the gadolinium ion in a cage, which is thought to prevent its dissociation. Linear agents, on the other hand, have a flexible open chain that has a lower tendency to hang on to the the gadolinium ion.

Theoretically, of the four combinations possible (see table), the ionic cyclic agents should provide the best protection for the gadolinium ion, and the non-ionic linear agents would provide the least protection. In vivo studies, while confirming the low stability of the non-ionic linear agents, have not found a significant difference in stability between ionic and non-ionic cyclic agents.

With the revised FDA labeling, the use of Magnevist, Omniscan, and Optimark is contraindicated in patients with acute kidney injury or chronic, severe kidney disease (GFR < 30 mL/min/1.73m²).

	Ionic	Non-ionic
Linear	Ablavar (gadofosveset trisodium) Eovist (gadoxetate disodium) Magnevist (Gadopentetate, Gd-DTPA) Multihance (Gadobenate, Gd-BOPTA)	Omniscan (Gadodiamide, Gd-DTPA-BMA) OptiMark (Gadoversetamide, Gd-DTPA-BMEA)
Cyclic	Dotarem (Gadoterate, Gd-DOTA)	Gadavist (USA)/Gadovist (Europe, Canada) (Gadobutrol, Gd-BT-DO3A) ProHance (Gadoteridol, Gd-HP-DO3A)

Gadolinium Release and Nephrogenic Systemic Fibrosis

A concept that is important in stability of gadolinium chelates in vivo is transmetalation. This is the process of gadolinium release through replacement by other serum cations (e.g., zinc, iron, copper, and calcium). Zinc's relatively high serum concentration (55–125 μmol/L) makes it the major player in transmetalation. The zinc replaces the gadolinium ion and is excreted in urine as zinc chelate. Measurement of zinc chelate can be used as an indicator of the amount of free gadolinium.

Copper's low serum concentration, calcium's low affinity to organic ligands, and iron's strong bond to ferritin and hemosiderin limits their availability for transmetalation with gadolinium ions.

The released gadolinium ions, in turn, bind to endogenous anions such as phosphate, citrate, hydroxide, and carbonate and deposit in tissues as insoluble compounds. It is thought that the release of cytokines in response to phagocytosis of these insoluble compounds by macrophages is responsible for the development of nephrogenic systemic fibrosis (NSF).

One such cytokine, transforming growth factor beta, is a potent fibrogenic agent that attracts circulating fibrocytes. These deposit in the dermis and other organs that contain the insoluble gadolinium deposits and mature into fibroblasts. The fibroblasts then deposit collagen in the affected organs, leading to fibrosis.

References

Morcos SK. Extracellular gadolinium contrast agents: differences in stability. Eur J Radiol. 2008 May;66(2):175-9.