Gd in humans: Where's the Gad?

For all heavy metals (actually true for all toxins), where's the metal is an important question, and as we gain in expertise in management of the toxicity we have to consider the following issues:

(I will use Gd as the heavy metal, but any heavy metal can be substituted in)

1. total body content of Gd

2. Distribution in organs and tissues

3. Within the organs, where is the Gd present

4. How much is extracellular and how much is intracellular.

5. How freely does Gd move out of, and between organs

6. Which cells are the heavy metal in.

7. How freely does it move between intracellular and extracellular location.

8. What happens to the Gd when the cells containing them die? Example macrophages.

Re-equilibration of metals is a subject unto itself and will be described separately.

Much of this blog is now theoretical. I base it on working with GBCAs in clinical research for 34 years. Reading the majority of the literature on the 50 year history of Gd as an imaging agent for 18 years. So this is about as good as it gets for anyone who describes themselves as an expert. Yet I have to caution this is largely based on theory and not fact

So these are my estimates on the 8 points, Could be considered the Hateful 8.

1. By month 3, 95% of the administered dose is eliminated by renal route and additional hepatic route for Multihance, Eovist/Primovist (and Ablavar). By 1 year 2% of that administration is retained for the linear agents; 1.5% for Gadavist; and 1 % for Prohance, Dotarem/Clariscan, and probably Gadopiclenol. 1% of the total remaining is eliminated each year (Eg; 1% of the 1% retained of Prohance). So negligible continued elimination for life.

2. For Gd the largest reservoirs are bone (also most stable) and skin, followed by soft tissue organs (includes brain), muscle, negligible andin fat.

3. Gd is generally administered by fast iv injection (2 ml/sec). This is therefore unique in its pattern of intra-organ deposition. Fast injection, drives the metal into the extracellular matrix (ECM), so proportionally much more of Gd is present in the ECM than with other metals. My present estimates: 10% in circulating immune cells (primarily macrophages, but also related phagocytizing immune cells); 50% in vessel endothelium (primarily capillaries, small arterioles, and small venules); 30% in the ECM (AKA interstitial tissue).

4. Presently, except for macrophages, the majority of the Gd is in the extracellular space. I estimate 80%

5. Movement between organs largely depends on how tightly the Gd is bound in the tissues and organs. Movement between soft tissue organs is relatively unimpaired. Movement from the tightly bound location in bone to soft tissue organs, generally requires the involvement of chelation. Chelation removes Gd is less tightly bound locations, and subsequent on the basis of le Chatelier's principle, Gd moves from bone to soft tissues.

6. With multihance and eovist/primovist some intracellular retention is present in hepatocytes, because intra-hepatocyte uptake is how the agent is eliminated in the bile to begin with. The unknown question to me presently, is how much of Gd is intracellular in other cells in the body? I suspect that cells with a supportive role are much more likely to contain Gd (and probably serving as a protective mechanism) then the critical organ-specific cell. For most individuals, the intracellular localization in the brain is of greatest concern. Of the Gd that is intracellular in the brain, probably 70% are in vessel endothelial cells, 27 % in brain supportive cells (eg: microglia and astrocytes) and 3% in neurons themselves. The reader should note that of all the estimates I derive in this blog, this intracellular localization I am least confident in.

7. Many/ the majority of cations relatively freely move between intra- and extra-cellular spaces, and extremely rapidly. The best known of these cations doing this are sodium (Na) and potassium(K). This ofcourse depends on how captured the cation is in intracellular organelles, such as mitochondria, endoplasmic reticulum and Golgi apparatus. Na and K are free moving. Gd if/when intracellular may be more durably contained.

8. Gd released from death of cells like macrophages, likely experiences three subsequent movements, i) another macrophage picks it up, ii) it becomes attached to vascular endothelium, likely principly in the spleen, and iii) it is eliminated in urine.

   
   

Richard Semelka, MD