Is it important if Gd is in the intact chelate or if it is unchelated? It appears clear with NSF that it is important if Gd is in the intact chelate (should not get NSF) or unchelated (may cause NSF), and with GSC (notably Gd deposited in brain), however it does not appear to be important in acute hypersensitivity reactions or GDD. In many respects my current thinking is that GDD is essentially a hypersensitivity reaction which over time recruits chronic immune cells into the response.
After decades of recognizing the existence of acute hypersensitivity reactions to Gd it is not clear what cells of acute reactions are responding to: is it the intact GBCA, is it released Gd, or something else. It should not be released Gd as it occurs with all GBCAs, even the most stable (Dotarem) which should be fully intact. Even with the weaker chelates, these also should be fully intact when the host reacts to the GBCA (often within minutes). So clearly Gd is present in the intact chelate, and the host is reacting to it. My theory is that the host immune cells can recognize the presence of Gd, either at a distance from the electrical charge, or by insinuating itself into the chelate and identifying the Gd within.
This would also be the situation with most cases of GDD; when the disease arises within minutes, hence all GBCAs will be intact, and also because this disease occurs with perhaps equal incidence with macrocyclics, which should be fully intact, and with linear, that will be in a mixed population of intact chelates, and Gd bound to other substances. I believe the immune cells are insinuating themselves, like amorphous amoebas, into the molecules to recognize the Gd.
In a similar vein of uncertainty, we recognize that Gd can substitute itself for Ca in the vast array of physiologic reactions throughout the body, notably substituting for Ca in bone. SO it makes sense that with linear agents, the agent may come apart, and the released Gd then enters bone as a substitute for Ca. But how does this explain that with macrocyclic agents, the fully intact chelate is deposited in bone? The earliest papers on this subject, by Gibby and White, in 2004 and 2006 describe intact Prohance in bone. How is this happening? Presumably again there must be a tropic effect of recognizing the Gd even in an intact GBCA, that causes it to go to bone.
At the other end of the spectrum: why does iv DTPA result in higher urine Gd content in subjects who have received just macrocyclic agents, as the Gd in chelates will not be able to directly substitute in to the administered DTPA. In our peer-reviewed papers one possibility we entertained is that DTPA is able to lever the fully intact GBCA out of tissues (possibly also out of bone) and into the blood circulation for elimination.
In short, we don't know why intact chelate appears in a number of settings to behave as if the Gd was in isolation, but it does. This uncertainty in the scientific community has existed for decades, long before GDD came to be recognized. My current thinking is that cells in the host immune system is able to insinuate itself into the chelate molecule to recognize the Gd, with almost equal efficiency as if Gd was in a more exposed circumstance.