Absorption and selective distribution

A key property for an oral iron chelator is its ability to cross biological membranes enabling it to be absorbed from this intestinal tract. The above property however will also endow the molecule the ability to efficiently penetrate the blood-brain barrier. For this reason, it is important to ensure that chelating agents are directed to target tissue such as the heart and liver whilst minimising exposure to critical organs/cells. 

Most drugs enter cells by simple diffusion through the hydrophobic region of the cell membrane and consequently uncharged drugs permeate more rapidly 

Clearly, for oral activity to be achieved, the chelator must also be designed so as to resist the acidity of the stomach and enzymatic cleavage. Thus esters, amides, Schiff-base ligands and simplex hydroxamates should be avoided. 

Metal chelate complexes should be excreted rapidly in the faeces or urine with no redistribution of iron from relatively non-toxic sites such as the liver, to more harmful ones such as the heart. Complexes formed intracellularly should not accumulate within cells, but should leave cells freely. In the case of liver cells this should result in significant excretion of iron in the bile. Clearly this biliary iron-chelator complex should not then be reabsorbed from the gut. 

In principle the redistribution of iron can occur if both the chelate and the iron complex freely cross membranes. However, if the free chelate permeates more readily than the complex, a large proportion of liver iron will be excreted via the bile and will thus be unavailable for redistribution to other tissues. May and Williams [28,29] have suggested that an ideal chelator, in addition to 

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