Heavy Metal Chelators. Additional considerations: Route and Rate of Exposure; Mud Tracks; Bioavailability. Multimetal Deposition Disease

Besides the critical aspects of safety, stability, and documentation it works (elimination), the additional important considerations are route and rate of exposure; the mud tracks of the exposure; and bioavailability.

Route and rate of exposure,

The use of DTPA perhaps best illustrates these points. DTPA is FDA-approved for the removal of Plutonium, Americium, and Curium, all radio-active heavy metals. Some of the earliest use of DTPA was for accidents in radiation plants, and the notable exposure was inhalation of Plutonium. At the time they utilized the most empirically logical delivery of DTPA, by aerosolized inhalation of DTPA. In setting like aerosolized exposure additional use of cutaneous (skin) application of chelator seems empirically obvious.

The most recent widespread use of DTPA is in off-label application for Gd and lead. The vast majority of Gd exposure, in this case, which is near unique for heavy metals, as medical administration is the form of exposure, is by intravenous administration of a bound (chelated) form of Gd. These are called GBCAs. Critically though the GBCAs are administered as a fast injection, generally 2 ml/sec, and not by a slow drip rate. The reason for the fast injection is that it drives the Gd into the deep extracellular matrix (ECM), also called interstitial space) so that well vascularized cancers, and other processes such as inflammation show intense enhancement (brightening on a type of MR sequence (T1 sequences). Drip infusion, tried in the earliest days of GBCA use (early 1990s) does not reveal that clear distinction of brighter appearance of cancers compred to background organs. This brighter appearance not only allows more confident diagnosis, but at times the only way to see these diseases. So the reason for fast administration of GBCA is beyond question. Hence administration of DTPA should follow not only the route (intravenous) but the rate (fast bolus) as the GBCA had entered the body. There is though roles for slower drip infusion of chelator, such as extreme sensitivity to Gd, the subject does not want to receive steroids to manage Flare, and later in a series of chelations, in which a fair amount of the Gd is now from re-equilibration and not just from the original administration.

Most other heavy metals have been incorporated into the body from oral digestive tract exposure, example lead. So although iv administration of a chelator like DTPA is presently necessary (since there is no oral form of DTPA yet produced), and intravenous administration of an active agent ensures 100% bioavailability; the clear benefit of intravenous administration is not as strong, and oral administration of a chelator more closely matches how the heavy metal exposure occurred.

Mud Tracks.

Mud trucks is a more pictorial description of the above consideration of route and rate, as it is more visually evident to understand that how the heavy metal exposure occurred also reflects how the heavy metal is deposited in the body. The mud tracks are thicker along the path of administration.

To illustrate this difference: Gd given by intravenous administration develops as its mud tracks Gd deposited along vessels arteries, capillaries, veins through the entire course of the vascular system throughout the body, probably with the densest concentration (thickest mud tracks) along capillaries and small veins (venules) which would experience more prolonged contact and transfer of Gd between vessel and tissue and vice versa. Then ECM mud tracks due to the fast injection rate. The mud tracks of lead would then follow how it was incorporated, so mud tracks along the digestive track, most along small bowel, then the vessels that take blood from the small bowel, small branches of superior mesenteric vein, to portal vein to liver, so the thickest mud tracks would follow that distribution.

Bioavailability

This property describes of the amount of chelator delivered how much is actually incorporated into the body. So for active drugs (DTPA, EDTA) this refers to primarily how effective has the agent that is delivered been incorporated into the body. The most common circumstance is of an orally administered drug and generally expressed as percentage. So of the 100% of drug taken orally, what percentage is actually incorporated. Ideal would be >80%, very good around 50%. But this property may not be a deal breaker, so if only 5% of drug is incorporated then increasing the amount in the body systems generally would simply mean taking more of the agent. The same analysis would be for skin application. Lung aerosolized agent generally would achieve much higher bioavailability, since the membranes in the lung separating aeration and blood vessels is both thinner and more porous than these in the digestive tract.

Prodrugs (drugs that need to be converted to active form) contain the additional variability of bioavailability is they depend on the health of the organ that makes the conversion to active form. Both DMSA and DMPS are converted into active form by the liver, hence a disease liver (acute or chronic hepatitis, cirrhosis) would be much less capable of making the conversion hence much lower bioavailability.

Multimetal Toxicity/ Deposition Disease

The clear advantage of intravenous DTPA over other chelators is that it has higher stability with more heavy metals. So at the present time with DTPA being solely administered by iv (although aerosolized also effective, but presently not generally used) even when metals may have been incorporated by oral/digestive tract route (lead Cadmium) if Gd is also part of the picture, since DTPA has high stability with Gd (21), lead (18.6) and Cadmium (19) with this combination much higher than for the other available chelators, then iv DTPA would be the prefered agent to use.

Richard Semelka, MD