Speciation 98: Abstracts

The toxic and essential metals will be reviewed, to appreciate the overlap between these two groups. The influence of in vivo valence state on the toxicity of some metals and their ability to be chelated will be discussed.

The desired properties of chelators will be reviewed, as follows, with consideration of the impact of metal and chelator speciation on chelation efficacy and safety. This will be illustrated with results obtained with various toxic metals, particularly aluminum.

The chelator should have high selectivity. There are no metal-specific chelators. The hard-soft acid-base classification of metals and chelators will be mentioned as an approach to match donor-acceptor properties to identify a potentially effective chelator for a specific metal.

The stability of the complex between the chelator and the target metal of chelation, compared to other metals, is one factor influencing chelation efficacy and safety. The use of competition experiments, assessing the ability of a chelator to remove the metal from another (endogenous) ligand, will be illustrated with results of the ability of chelators to mobilize iron and aluminum from transferrin.

Structural modifications which influence the site of chelation can greatly influence chelation efficiency. This will be illustrated with substitutions on EDDHA, showing increased aluminum chelation by ligands with electron withdrawing groups and by comparison of racemic- and meso-DMSA to chelate cadmium, mercury, and lead.

The role of denticity will be introduced. The advantages of chelators that fulfill the optimal coordination requirements of the metal will be illustrated with results showing increased efficiency with hexadentate and tetradentate over bidentate chelators for aluminum, for which the preferred coordination number is 6. A further advantage of fulfilling the coordination requirements will be illustrated with results suggesting that this reduces the ability of iron to produce oxidative damage.

The chelator should distribute to the site(s) of metal storage. Most therapeutic applications benefit from oral bioavailability. In the absence of a carrier or transporter, increased lipophilicity promotes oral absorption and distribution to metal storage sites. The goal of chelation is to decorporate the metal, reducing its toxicity. Modeling most metabolic transformations, this should be accomplishable by increasing hydrophilicity, to increase excretion of the metal-chelator complex. The influence of chelator lipophilicity on chelation safety and efficacy will be illustrated with examples of toxicity or low excretion of lipophilic aluminum-chelator complexes.

Therefore, the speciation of a metal can influence its pharmacokinetics, toxicity and ability to be chelated and the speciation of a chelator can influence its ability to effectively and safely complex and eliminate the metal.

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