HOPO and DTPA. Discussion of Chelators.

The symptoms of GDD are relatively consistent between all Gadolinium contrast agents, regardless of how stable they are or their primary routes of GBCA elimination, renal or hepatobiliary.

DTPA chelation.

DTPA is one of the ligands used for MR contrast agents (basically Gd-DTPA is Magnevist), so its behavior is something that radiologists are very familiar with. GBCA ligands are essentially cation binding molecules.. DTPA chelation is essentially the same process serving as cation exchange molecule. DTPA binds Gd directly in the majority of linear GBCA agents. The difference with very stable agents like Dotarem/Clariscan and Prohance is that they are likely still fully intact in the body, and the chelator DTPA acts to tug them back into the circulation where most passes out in the urine and some, maybe 10% gets redistributed. So the effectiveness of removing Dotarem/Clariscan and Prohance is less, as tugging removes less Gd then cation exchange does. The good news is that these macrocyclic agents leave less agent behind,, which counteracts somewhat the bad news that chelation is less effective at removing it, So in balance these factors are a wash with agents that leave more agent behind but are easier to remove because they undergo cation exchange: Omniscan, Magnevist, Multihance to name the most common.

So with DTPA chelation then the Gd removal from the body follows the course of most GBCA agents, which is by renal elimination. DTPA . Eovist/primovist, would though experience 50/50 renal/ biliary elimination.

Fecal Gd elimination of most GBCAs with DTPA chelation should not occur, Some GDD individuals claim that it has occurred following oral zeolite use, by showing elevated fecal Gd testing. However, as described in a reason blog, the finding of fecal Gd is from the zeolite. So zeolite is not recommended in GDD patients because it contains Gd.

Since GBCAs have been administered by fast iv administration, the initial chelation is probably most effective if it reproduces this method of administration. This follows the mud tracks of the Gd left behind. Most of the Gd deposited in the body is in the extracellular matrix (ECM; AKA interstitial space) and deeply embedded because of how it was administered. So using the chelator to chase it down in the same fashion makes the most sense. Perhaps after 5 chelations, a fair amount of the remaining Gd may now be the result of re-equilibration,so not primarily in the deep ECM.

Finally testing for Gd removal with 24 hour urine makes the most sense with DTPA and other cation-exchange chelators (eg: other MR contrast ligands).

HOPO chelation.

HOPO is created as different molecular structures. The HOPO species used for metal removal works in a different fashion. It is not a cation exchange chelator. It may be best described as an electrostatic bonding agent. It does not cation exchange, like DTPA, so it does not exchange either Ca or Zn to pick up Gd, it just picks up Gd and other heavy metals. The final molecule is lipophilic and because of that appears in large measure to be eliminated by the biliary system. In my experience it also does remove Gd by renal route. So fecal elimination is likely quite prominent, and may be the dominant elimination pathway with HOPO. I am not keen to test feces, so probably when I use HOPO clinically in patients I would continue to test with 24 hr urine. I would have no problem if patients test their feces on their own. The FDA testing that is currently being done is not centered on Gd (it is focused on Lead), so we likely will not get a sense from these phase trials how much Gd-HOPO is eliminated in urine compared to bowel. For instance we know that renal/fecal elimination of eovist/primovist is 50/50. HOPO may do the same. It may be then determining this relative ratio may have to be done in phase 4 studies, ie: after HOPO is FDA approved.

One does have to wonder if oral HOPO is mainly then picking up superficial tissue Gd and not deep ECM Gd, because oral administration will not emulate the deep concentrated entry of the chelator that fast bolus iv chelation results in. My impression is deep ECM Gd is the most symptomatic.

Combination DTPA/ HOPO chelation.

Likely the most effect regimen for chelation removal of Gd (which means removal of Gd) is the combination of starting with several sessions of iv DTPA administered as iv boluses, followed by oral effective chelator like HOPO.

Richard Semelka, MD