Speciation 98: Abstracts

In hereditary anemias such as thalassemia, iron overload is the joint outcome of excessive iron absorption and transfusional siderosis. While iron absorption is limited by a physiologic ceiling of about 3 mg/d, plasma iron turnover in thalassemia may be 10 to 15 times normal, caused by the wasteful ineffective erythropoiesis of an enormously expanded erythroid marrow. This outpouring of catabolic iron exceeds the iron binding capacity of transferrin and appears in plasma as non-transferrin-plasma iron (NTPI). The toxicity of NTPI is much higher than of transferrin-iron as judged by its ability to promote hydroxyl radical formation resulting in peroxidative damage to membrane lipids and proteins. In the heart, this results in impaired function of the mitochondrial respiratory chain and abnormal energy metabolism manifested clinically in fatal hemosiderotic cardiomyopathy. Ascorbate increases the efficacy of iron chelators by expanding the intracellular chelatable iron pool but, at suboptimal concentrations is a pro-oxidant enhancing the catalytic effect of iron in free radical formation. NTPI is removed by i.v. DFO in a biphasic manner and reappears rapidly upon cessation of DFO, lending support to the continuous, rather than intermittent use of chelators. Unlike DFO and other hexadentate chelators, bidentate chelators such as L1 may produce incomplete intermediate iron complexes at suboptimal drug concentrations. Although L1 is able to induce a negative iron balance, its use is associated with significant toxiciy, the most important of which is agranulocytosis. However, recent observations also raise concerns regarding the ability of L1 to induce sufficient depletion of tissue iron to offer protection from critical organ damage in a substantial fraction of patients. Among the other new chelators that may be suitable for clinical use, HBED and dimethyl-HBED are presently being evaluated. Another promising new chelator is IRC011, a substituted cyclic polyaza compound, with preferential interaction with the toxic non-transferrin plasma iron (NTBI) released from RE cells. Safety and efficacy are major considerations in the selection of new chelators. These are determined by the nature of their interaction with iron. Thus, hexadentate chelators would be always preferable to bidentate or tridantate chelators. The partition coefficient determines ability to cross lipid membranes and lipophilic compounds penetrate cells with relative ease. Prodrugs can be made less polar than their active derivative and their intestinal absorption may improve markedly. Because of their gradual release and absorption, their overall effect may be improved several-fold. Better understanding of the pathophysiology of iron toxicity and the mechanism of iron chelation is vital for the development of improved strategies of iron chelating therapy.

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