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Chelators for GDD Revisited. March 2021

This is intended as a brief blog, and in the not too distant future I will expand it with including the thermodynamic/stability constant values.

This seems to be a topic of continued misunderstanding, even by experts. It is also interesting that radiologists and other physician imagers, who understand that thermodynamic stability (stability constant) is the crucial aspect of creating a GBCA, do not understand that the same factor is true for a chelating (decorporation agent). It is widely understood that MR GBCA agents with lower thermodynamic stability: Omniscan and Optimark, are the most likely agents to cause NSF due to their lower thermodynamic stability (and to a lesser extent geometric structure; ie: they are linear). These also happen to be the agents that show high signal in the dentate nucleus and globus pallidus, compared to agents. The European Medicines Agency has banned the use of these agents, due to their lower thermodynamic stability. They are more likely to break down in vivo (that is inside your body) releasing Gd, which everyone understands is not a good thing.

The same is true of chelators (decorporation agents). I will put it again in bold in case you missed it:

the same is true with chelators. Chelators with lower stability constants with Gd should not be used to remove Gd.

This point is also not understood: All chelators, even those used for other metals, also move Gd. The problem is that much of the moved Gd, because the chelator does not have high affinity for Gd, will result in redistribution of Gd immediately back into the body. This means that agents such as DMPS and DMSA will pick up Gd and re-release it immediately back into the body. So Gd will be picked up from large reservoirs like the skin, and then re-release Gd, which now may travel to the brain or other organs. This can be a very bad thing.

So MR agents are not Gd-DMPS or Gd-DMSA or Gd-EDTA - because these would be extremely unstable GBCAs and result in massive internal deposition of Gd, so the amount of retained Gd from the contrast agent would be in the order of 50% of the administered dose. This would be a very, very bad thing. The same is true for chelators (decorporation) agents. This should be a very simple straightforward understanding. I am not sure why it is not.

What is also not understood is that based on these same stability constants DTPA is the best of these chelators to remove other heavy metals, like Pb (lead) and Hg (mercury). It is all about the stability constant.

There actually are text-references that list decorporation molecules (chelators/ligands) and multiple metals/cations and their stability with them.... large reference texts with multiple entries. If certain chelators are not listed for Gd it is because they have not been tested yet for stability - in large part because scientists have considered that the results will be poor.

What is also not understood, the binding cation also plays a large role: a cation with low stability with DTPA will release DTPA more readily, and the DTPA will pick up more cations and metals (that is native cations and metals in the body, (like Mg, Mn, Fe, and Zn, in addition to all heavy metals like Gd). Cations with high stability with DTPA will not release DTPA to cations with lower stability (so will not pick up native metals). So: Ca-DTPA does pick up more Gd than Zn-DTPA because it more readily releases Ca, but also picks up Mn, Mg, Zn. If repeat chelations with Ca-DTPA is done at high frequency, such as daily, this can then result in serious metabolic imbalance... I never do this high repetition because of this concern. Conversely, Zn-DTPA is more strongly bound so does not release DTPA to Mn, Mg, Fe. So will not have the same potential to cause metabolic imbalance. The downside is about half as much (or less) Gd is removed as a reflection of the higher stability.. Whether either Ca-DTPA or Zn-DTPA is used, both have the same end result stability, so both retain Gd well and have very minimal re-release of Gd.

Ofcourse it is optimal to have a chelating agent that can also be administered orally. We have to wait for HOPO and oral versions of DTPA and similar molecules. In any even though, chelation may need to start with iv therapy, for the chelator to follow the path of the administered Gd: like a tracking secret agent to pursue a criminal: following the path.

Topical preparations of chelators may be a different matter, and weaker chelators may be reasonable to employ. Firstly re-release may occur on the skin surface, or if re-release back into the skin, then the Gd is not released back into the circulation. The re-release suggests that cream removal at a time like 5 minutes after administration, with rinsing with a salt solution may make empirical sense.

So stability is a knowable property. If the chelator considered for use does not have a published stability constant for Gd I would not use it to remove any metal if Gd is part of the picture... Think of it in the same terms as an imaging agent. If 5 GBCAs have published thermodynamic stability, would you use a 6th agent in which the thermodynamic stability is unknown and likely low? No, it would be crazy to do that... The same holds true with chelators/decorporation agents. It is all about stability: stability of the chelating molecule, its stability with the manufactured cation, stability of chelating molecule with the intended target (and all other targets- meaning Gd), and the stability of the targets with what they are bound to in the body. Thinking out the stabilities is absolutely crucial for optimal chelation.

I intend to re-release this blog with stability constant data in the future.

Richard Semelka, MD

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