How a Chelator Should be Administered. Illustrated by iv DTPA and Gadolinium Deposition.

This is a revisitation of prior blogs. I had thought the concept was resolved, but like Freddie Kruger somehow miraculously they re-appear.

I use the principle of how the GBCA (or other heavy metal) was delivered to begin with, when determining how to administer the chelator. GBCA is administered as a bolus injection at 2 ml/sec. Originally both GBCAs for MRI, and prior to that Iodine contrast (IBCAs) for CT were initially administered by drip injection. Within 2 years for both agents, where research was done comparing drip with bolus injection, injection was found superior to enhance normal tissues and also various forms of disease, most importantly malignancies. This is because intense contrast enhancement in the capillary phase of tissue and tumor stroma are maximized. Normal organs are enhanced most intensely, vascular tumors are enhanced most intensely, and may only be seen in this early phase, and the enhancement difference between normal organs (brighter) and hypovascular tumors (darker) is maximal. So that is how the GBCA was delivered to begin with and why. The upshot is that this is where the majority of Gd is retained in the body, in the deep interstitial tissues surrounding vessels (specifically pericapillary/ perivenuole). In all organs and tissues: in skin, brain, lungs, kidneys, liver, bone,  etc.. We essentially emulate with the DTPA chelator, how the Gd was delivered to begin with, and hence retained: by bolus injection. This makes pure empiric logic. 

The absolute  importance of bolus injection is probably reserved for metals that have been administered by that bolus iv route. So in metals that have not been incorporated in the body in that fashion, rapid bolus injection is possibly not essential. So if the heavy metal was acquired by ingestion, inhalation, skin absorption, the retained metal will not be in such a dominant deep interstitial perivascular location, therefore drip iv infusion, oral intake, and aerosolized delivery may all work. In fact, how the metal was acquired, following that pathway with the chelator, again makes good empirical sense: the mud tracks of the heavy metal follow the path it was administered. The product insert for DTPA may describe administration as a drip technique, because it was originally marketed and FDA approved for plutonium and other radioactive metals that were not acquired by rapid bolus injection, but rather by some combination of inhalation and skin absorption. That explains some of the earliest use of DTPA for radioactive metal workers was with aerosolized administration. 

I will finish with my vision of the future. My opinion is that ultimately the best form of chelation for Gd, factoring in everything: effectiveness, safety, cost, patient comfort is to start with 3 sessions of bolus iv injection of DTPA or comparable (by comparable I mean a more stable chelator like BOPTA, and not a less stable chelator, like EDTA) then followed by an oral chelator like HOPO (or oral DTPA, BOPTA, and as yet undeveloped). The first 3 iv sessions will remove much of the dominant location perivascular Gd, and over time and re-equilibration with chelation, the distribution will not be that deep interstitial in dominance, but more broadly distributed, so oral administration should do a sufficient job at continued removal.

I have used, studied, researched and published major papers on GBCA and administration for 36 years. I have used, studied, researched and published major papers on DTPA chelation for 8 years... and have studied now chelation with other chelators for 6 years. Everything I do and recommend in chelation (and imaging) is based on significant and carefully considered experience and expertise.

Richard Semelka, MD