Creating the Frankenstein Monster: Another GBCA

The question often comes up: what is DTPA (in fact what are any chelators) doing with Gd? The answer is recreating in vivo (literally in life - in actually in one's body) a GBCA. A number of sufferers, most in fact, recoil in horror at the idea we are recreating a GBCA, the thing that made them sick to begin with, but now in their body. In deed it is like bringing the Gd back to life, taking it out of the tissue and creating the Frankenstein monster: another GBCA.

Once recovering from the shock - here is the scientific and reassuring basis. Gd-DTPA is essentially Magnevist (the new life) and we are creating that. It turns out that these MR contrast agents are among (or the) most stable forms of Gd to facilitate carrying it out of your body - through the blood stream - to the kidneys - out in urine. As I have said before, Schering (now morphed into part of Bayer through acquisition years ago) tested back in the 1980's, and published in the peer-review literature, research on a number of ligands (essentially chelators) to determine what chelate to manufacture as a GBCA. Among what they tested were DTPA and EDTA. EDTA was found to be far less stable than DTPA with Gd, so not pursued as an MR contrast agent. This also is why I have stated, perhaps atleast 10 times now, in various blogs - I would never use EDTA to chelate Gd, now that we have DTPA - it is not stable enough and will re-release a fair amount of the Gd back in the body. Gd-DTPA is cheap to make, a cheap ligand, and really quite stable - so Schering developed it and marketed as Magnevist. This agent has more than 100 million doses given, and overall, comparing it to other medications of all types, it is quite safe. So when I am asked how often has DTPA been used to chelate Gd in humans the answer is 100 million times, compared to maybe 500 with EDTA.

The circumstances are also much different from when the GBCA was originally given - the chelation process and surrounding period are designed to emphasize removal of Gd-DTPA: it is given with a fair volume of normal saline, and patients are instructed to drink lots of fluids (I recommend especially alkaline water, to enhance stability of the chelate). The problem for individuals who develop GDD after a GBCA, a number of them had been dehydrated at the time of the GBCA injection. Dehydration very bad, excess hydration (what we do with chelation) very good, to remove a GBCA or the Frankenstein Gd-DTPA from the body.

Also, if on average 1/100 of the amount of Gd that was injected in the body, originally as the GBCA, now remains during the time of chelation, at best we hope to recreate 1/100th of the amount of GBCA that was originally administered. Thinking of how little this is compared to a dose of a GBCA administered for MRI two things should strike the reader: 1. it is amazing that such a small dose can create a Flare reaction, and 2) if such a small dose can cause so much symptomatology of a Flare how much can a full dose of GBCA do? Answer a tremendous amount, especially when the Flare occurs during the removal of Gd (so less Gd left in the body ultimately, hence long term less cumulative symptoms) and GDD occurs during the accumulation of more Gd in the body (so food for more cumulative symptoms). This explains why I am focusing so much on the importance of recognizing when one has early signs of GDD - repeat GBCA injections cause about 100x the equivalent GDD symptoms as Flare, and also have the unfortunate circumstance of adding more Gd burden to the body.

Is all the Gd that is removed by chelation with DTPA in the form of Gd-DTPA?

My opinion is probably no. Otherwise how can we explain that following chelation with DTPA there is increased Gd in 24 hr urine (probably about 4 x more than baseline) when the sufferer only received macrocyclic GBCA, which should be still in intact GBCA. My explanation still has not changed: either the host immune cells have broken down the macrocycles, or the DTPA is levering intact chelate out of the tissues back into the blood stream, or a combination of both. I will add a third possibility (related to levering) that DTPA acts as a carrier molecule to carry the intact chelate through the bloodstream to the kidneys into the urine. A fourth possibility had been suggested to me actually by an astute sufferer, but this would relate only to (primarily to) Gadavist: could DTPA be transmetalizing with the ligand of Gadavist, DO3A-butrol (generic name Gadobutrol, chemical name: Gd-DO3A-butrol), as Gd-DTPA has a slightly higher thermodynamic stability than Gd-DO3A-butrol? My opinion, based on discussions with scientists from Bayer, probably not because the kinetic stability of Gadavist is vastly greater than that of Magnevist, and they consider that with macrocyclics, kinetic stability is a much more important stability factor than thermodynamic.... That being said of course it would be interesting to test this.

What species of Gd is being reconstituted into Gd-DTPA?

Chemist PhDs involved with GBCAs have considered that in the body, Gd exists in generally 3 species: intact GBCA chelate, inorganic salts (mostly Gd-Phosphate, next most common Gd-carbonate, then likely a considerable number of others) and in macromolecules.

Intact GBCA should remain as intact GBCA and if removed is levered out of tissues. Inorganic salts: can DTPA break the bonds of an inorganic salt? It seems doubtful as these should be much stronger than the bonds of a chelate. So if this species is removed it has to be levered or more likely carriered out by DTPA. Macromolecules. Whence protein or polypeptide(or maybe lipid) macromolecules? Logically these could be part of the immune system response to GBCAs, either as already existing circulating or interstitial blobs of material, to soak up unwanted items like so many sponges, or actively created by immune cells, or both. If created in response to the presence of Gd in the body, perhaps by circulating fibrocytes or other bone marrow-derived cells. This may then be part of the development of light chain proteins described in Gd toxicity. This also I described in an earlier blog.

So true reconstituted Gd-DTPA, the Frankenstein Gd, most likely must arise from this primordial goo of Gd bound up in macromolecules.

The species of Gd in urine could be readily tested to answer this conundrum.

From what body Reservoir is Gd removed by chelation?

As I have stated in prior blogs, most likely Gd is removed from reservoirs where it is less tightly bound and in large volume. So most likely skin and skin substrate and also from cells in circulation such as macrophages, and other cells, and this reservoir may be largely in the spleen (which congregates white blood cells).

The reservoirs of origin could be readily tested for by using a large animal model, with separately radiolabeled Gd and ligand (although radiolabeling only Gd would be sufficient for just this determination, separately radioloabeling allows speciation as well).

This blog restates a number of materials mentioned in earlier blogs. The repetition I think is likely extremely important. It is like learning a new language, repetition is important to remember what things are.This also provides scientists eager to make a valuable contribution and name for themselves what critical studies to do that have not been done yet.

The Frankenstein Gd, recreating a GBCA in your body with chelation.