GBCA types: linear and macrocyclic. How much of these does DTPA chelation remove?

With 6 years of dedicated evaluation of how much Gd is removed with DTPA chelation 0f the various brands of GBCAs, I am now in a confident position to describe how much of these agents is removed with DTPA chelation (the best available chelator).

There are actually two fundamental properties involved when assessing how much Gd is removed when certain GBCA brands are being chelated: 1) how effective is the chelator at removing a particular GBCA agent, and 2) how much of the dose administered of the GBCA is actually retained. On the individual's contribution side, certain sufferers may experience relatively more deposition in the most durable repository of Gd, bone, which would also decrease the amount of Gd removed with each chelation.

To address how much Gd is retained. In reading the great majority of the peer-reviewed literature both animal and human, I have estimated that the most stable GBCA agents Dotarem/Clariscan and Prohance probably leave 1 % of the amount administered behind at 1 year, and linear agents: Magnevist, Multihance, Omniscan and Optimark leave 2% (with Omniscan and Optimark leaving slightly more) and Gadavist leaves somewhere between those two groups Gd behind, probably 1.5%. These numbers are theoretically verifiable or challengeable, but this would be extremely difficult and expensive, and hence not likely to be done. So these are my estimates, arguably the world authority on the subject, so they are not too bad.

1. Linear agents. In chelating individuals who have not been extensively treated in the past by any agent, my observation is that Gd removal on 24 hr urine is generally in the range of 25- 60 mcg for a single lifetime GBCA injection for the linear agents and Gadavist from 3 months to at least several years post GBCA injection. The pre-chelation urine content usually is something like 1 mcg/ 24 hr at 3 months and drops to around 0 detectable at 1 year. When the pre-chelation Gd amount is measured at near 0 prechelation I will generally round up to 0.5 mcg/ 24 hr, because otherwise in judging the amount of Gd removal post chelation compared to pre-, represented as multiples, if pre is 0 then the multiples would be infinite, which is a silly amount to describe. But values are not uncommon for these agents in the range of 100 to 200 fold increased elimination compared to pre. The multiples of Gd removal comparing post- to pre-chelation amounts is generally in the range of 25 to 50 times more.

2. Gadavist. Gadavist behaves differently than the other macrocyclic agents. Its thermodynamic (stability constant) is much lower, in the range of linear agents, and its kinetic stability although much longer than the linears, is less than the other macrocyclics. It also has a higher causation of NSF than the other macrocyclics, although still much, much lower than the linear agents (Multihance though also exceedingly low causation). It has been proposed that the smaller cage of the macrocycle of Gadavist accounts for these properties, including that it is more likely to come apart compared to the other macrocyclics, and I ascribe to this theory. The amount of Gadavist removal with chelation. is generally in the range of the linear agents, where typical removal amounts post- Ca-DTPA chelation are in the 20 -50 mcg/ 24 hr range. The multiples of Gd removal comparing post- to pre-chelation amounts is generally in the range of 20 to 40 times more.

3. Dotarem/Clariscan and Prohance. With these macrocyclics, the thermodynamic stability (stability constant) and kinetic stability are both very high. It is therefore most likely that the agents are still fully intake GBCAs retained in the body when chelation is performed for many years, and likely the lifetime of the individual (and beyond). So there is no cation exchange (transmetallation) taking place. My theory is that the chelator is tugging the fully intact GBCA from the interstitial space back into the circulation, where the majority of the tugged-out GBCA is eliminated in urine (some re-distributed). With these GBCA brands it is therefore especially critical that not only the chelator have a high stability constant, but also that its charged locus be on the surface of the molecule to maximize the magnetic tug (think of the fridge magnet analogy I have used). Pre-chelation 24 hr urine Gd amounts are generally not noticeably different than for the above 2 groups, but post chelation can be considerably different. It is common that the post chelation urine values are in the mid yellow range (5 mcg/ 24 hr). The multiples of Gd removal comparing post- to pre- commonly are in the 2 to 5 fold range. It is interesting that despite this relatively low removal efficiency none-the-less patients respond symptomatically not so differently than the above groups where removal is in the 20- 50 fold range. With these individuals then symptomatic improval is the most important measure of how well chelation is going, and how many chelations are needed, because the starting point in this group, 3 mcg/24 hrs post chelation, is often in the range of what I used to consider stopping chelation for the above 2 groups. Some of the presence of low values may also reflect that less Gd is left behind. On some occasions the multiples of removal are more in the range of the above groups, and it is not clear why this has happened. The likely explanations are that the individual was misinformed what agent was used (probably not intentionally, but by general human error at the imaging center), or a more interesting possibility, the host immune system partially or completely disrupted the macrocycle. Note Dotarem and Clariscan are the same molecule,

There are interesting variations to the above, these numbers described generally refer to chelation from 3 months to 2 years post GBCA injection. When multiple GBCA injections are present then the numbers overall are all larger. When multiple different brands are used, then there is also a combination of removal efficiencies. Lastly, the timing of chelation that I find most intriguing is chelation within days of GBCA administration.

On a related topic, my opinion is individuals with severe acute hypersensitivity reaction (AHR) should be treated with the standard (steroids and antihistamines), as currently done, but they should also receive Ca-DTPA, likely with Zn-DTPA (and steroids and antihistamines) the following day, as a certain number of individuals will experience persistent Gd reaction progressing from AHR (primarily Mast cell reaction) into GDD (primarily T cell reaction). Very early chelation avoids the development of the host mounting a significant T cell response to the presence of Gd, and they have a high likelihood of avoiding GDD development altogether. Very early chelation will also likely not result in appreciable Flare with chelation, since significant Tcell cell replication in reaction to GBCA presence, and hence potential for significant Flare to chelation probably begins 10- 14 days post GBCA injection.. I am using the immune development time frame to vaccines, which is directly analogous.

Richard Semelka, MD