Stability of Gadolinium Based Contrast Agents (GBCAs)

July 25, 2018

 

There are two stability properties of GBCAs that are important to be familiar with as they relate to how well the GBCA stays intact: thermodynamic stability and kinetic stability. Thermodynamic stability refers to the proportion of GBCA that remains intact (chelated) versus dissociated in equilibrium. Kinetic stability refers to the rate or speed at which this equilibrium is reached. 

 

    In classic chemistry, thermodynamic stability is measured at a ph of 1 (extremely acidic), which does not reflect what happens in humans where the physiologic ph is 7.4. When thermodynamic stability is measured at physiologic ph this has been called conditional stability.

 

     Kinetic stability is generally reported at ph 1. It has not been reported at physiologic ph for GBCAs. The explanation for this, from the manufacturers, is that at physiologic ph the stability of macrocyclic GBCAs may be in the years, hence not practical to determine. Kinetic stability has been measured at ph 3 and ph 5. Hence when we see kinetic stability for the linear agents, especially the linear agents, with measurements in the range of 10 seconds, it is important to realize this is not measured at physiologic ph (where the kinetic stability would be in the range of days). Because it would suggest companies manufactured agents that fell immediately apart, and were also approved by the FDA as such. This is not the case. This stability of days would also be true for rechelated Gd-DTPA from the chelating agents Ca-/Zn-DTPA.

 

     Tables about thermodynamic stability of GBCAs were published for some years prior to the recognition of NSF, but radiologists did not understand the significance of what it may mean that Omniscan and Optimark have much lower thermodynamic stability than Multihance, Prohance and Dotarem, in relation to the development of NSF. This was understood in 2007.

 

     It was some years later that kinetic stability entered the discussion of stability of GBCAs. Some experts propose that the critical stability metric for macrocyclic agents is kinetic stability. So for example, although the thermodynamic stability of Gadavist is in the range of the weaker linear chelates, the kinetic stability at physiologic ph (could be termed conditional kinetic stability) is in the range of years. It is not clear why the thermodynamic stability is so low, and some have thought it is because the cage that Gd is in is relatively small.

 

     One insightful GDD sufferer raised the question since the thermodynamic stability is lower for Gadavist than for Magnevist (essentially Gd-DTPA, as in Gd rechelated with DTPA). Therefore a macrocyclic agent become converted to a less stable linear agent. The answer is almost certainly no, The reason is that the kinetic stability is so long for Gadavist, that it would not release the Gd in a time frame that DTPA could access it, so it would not be in a situation that the ligand DTPA and the ligand of Gadavist would be able to compete for a transiently unbound Gd. Gadavist remains intact for years by kinetic stability, so would not create the circumstance for competition for loose Gd, for the length of time DTPA would be in the body (days). It is extremely unlikely a linear ligand could dislodge a caged macrocyclic Gd. Note that ligand and chelator can often be used interchangeably, as these refer to the molecule that is attached to (or hopefully will attach to)  the Gd to bind it, and make Gd safe for in vivo (in live human) use.

 

    None-the-less this and other evaluations of ligands and heavy metals would be interesting, and important to examine. One interesting study was published earlier this year comparing the thermodynamic stability of HOPO compared to the ligands of all the commercially available GBCA ligands for Gd. But interesting to compare in the same setting if ligands can dislodge Gd (or other heavy metals)  from each-other or other binding agents. In the future it should be possible to create a formulary of chelators specific to various metals and cations.

 

    As a tangential point, it is critical when chelation is combined with supplements, that for the most part supplements should not be administered for atleast a few days (maybe 1 week) before or after chelation, as the chelator may preferentially pick up the supplement rather than Gd. 

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