Gadolinium. How much is left behind after GBCA injection?
There are many factors involved in determining how much Gadolinium (Gd) is retained in any one individual. Probably the level of renal function is the most critical; brand of GBCA is likely the second most critical factor, previous GBCA injections, gender, age, pre-existing renal abnormalities, immune system function, sweating ability, GI tract integrity, presence of other heavy metals, and probably many other to-date-unknown factors play a role.
Actual numbers are knowable, but expensive, dangerous and time-consuming to render in vivo numbers, making them difficult to impossible to generate. These could be acquired through separately radio-labelling Gd and its ligand, and examining all eliminated bodily substances, urine, stool, sweat, sputum. If done in an animal model it should be a large animal model that emulates humans as far as renal function, gastrointestinal tract function, and sweat function. Pigs don't sweat, so this model often used as a surrogate for humans would not be ideal. It probably would have to be a primate. In studying elimination products with radio-labelled Gd and ligand it would also allow for studying dynamic distribution pattern of GBCA following injection over time, and also study changing pattern of distribution after chelation, and comparing different chelation strategies. All this do-able and would be both fascinating and extremely important. but likely would cost atleast $10 million to generate meaningful results, perhaps $100 million and take 3 years till potentially in a publishable state. So is this going to happen? Almost certainly not. Also I would not personally be involved in animal research in larger animal models. I am ok with human experimentation as long as the risks are clearly explained and subjects adequately compensated.
So you will have to rely on my expert opinion. I have studied and read the great majority of the literature on GBCA safety and pharmacokinetics over the last 17 years, of literature on Gd dating back to the 1950s. So at this point I feel comfortable in providing expert informed estimates employing a synthesis of the majority of the literature. Bear in mind, using a variant of a famous quotation: expert opinion and 50 cents can get you on the bus. Having stated that caveat, I feel these numbers may be as good as it gets:
* linear nonspecific extracellular agents [lnea] (Omniscan, Optimark, Magnevist) probably twice as much are retained long term compared to the most stable macrocyclic agents [msma] (Dotarem, Prohance).
* hepatocyte agent (Primovist/eovist) benefits from a pronounced biliary elimination (50%of Gd removed by biliary system in individuals with normal renal function, and a much higher percent in those with renal failure) so probably even less left behind than stable macrocyclics.
* Multihance, because it has some biliary elimination, and Gadavist, macrocyclic but with lesser stability constant than the other macrocyclics, the amount left behind intermediate between linear nonspecific agents and the stable macrocyclics.
* all depositions double in the individual who has an eGFR of 30 (stage 3 renal function),
* elimination generally follows a logarithmic elimination pattern, similar in appearance to T2 decay on MR data.
*retained amounts of additional agents are all additive.
* loss of the ability to sweat likely adds 5% to the retention numbers, that is for example 5% additional to 1 % at 1 year, meaning 1.05%.
* all forms (speciation) of Gd are immunogenic, including the intact GBCA, but some forms may be more immunogenic (protein bound Gd) than others.
* all forms of Gd can be removed by chelation, either through transmetalization or electrostatic tugging.
So here are the numbers:
At 1 week approximately 10% of administered Gd retained.
At 3 months 3% of lnea and 1.5% of msma retained. At this time point all Gd is well bound in tissues, and negligible spontaneous elimination occurs (too small to measure by standard reported technique).
At 1 year, 1.5% of lnea and 0.75% of msma retained. At this point, spontaneous elimination in steady state is approximate 1% of the retained amount is eliminated annually. This means 1% of what is left is removed each year. This increases in circumstances of bone loss, such as major trauma or menopause, where Gd release from bone (the largest and most durable repository) increases, and at times dramatically.
It does not seem that this is much agent retained, and it isn't, but remember that a vaccine only contains 1 ml of fluid, and this is sufficient to completely affect your immune system, in most people for the good, in a small percent not so good to bad. I will address vaccines in a future blog.
Richard Semelka, MD