ALUMINUM TOXICITY--CHELATOR IDENTIFICATION AND SAFETY

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The long-term goal is to identify orally effective aluminum chelators with sufficient selectivity for Al and safety in animals to warrant testing in humans for the prevention and treatment of Al accumulation disorders. An ideal Al chelator will overcome the limitations of desferrioxamine, namely lack of oral efficacy, its relatively high cost and toxicity. Al accumulation results from parenteral administration of pharmaceuticals, prolonged consumption of Al-based phosphate binders by the renally impaired and exposure of industrial workers to Al fumes. The role of Al in Alzheimer's disease and other dementing disorders is under investigation and is controversial. A safe Al chelator with continued efficacy may help determine the role of Al in these diseases. The specific aim of the present application is to test the hypothesis that systemic availability, efficacy and safety of Al chelators relates to the lipophilicity of the chelator and the Al-chelator complex results in Al mobilization from storage sites to safely induce Al elimination and reduce Al toxicity. Eight analogs of 3-hydroxypyridin-4-one, a family of orally effective metal chelators, will be studied. Their lipophilicity ranges from below to above the hypothesized ideal range. The oral bioavailability of each analog will be quantitated in rabbits to determine the relationship between lipophilicity and absorption. The analogs will be tested in a single dose iv study in Al-loaded rabbits to determine in vivo Al chelation activity, evidenced by increased serum Al and biliary or urinary Al output. Selected orally absorbed analogs that increase Al elimination will be repeatedly administered to Al-loaded rabbits to ascertain their continued oral Al chelation efficacy as evidenced by increased Al elimination after repeated treatment and decreased tissue Al. Safety and ability to reverse Al-induced toxicity will be assessed by histopathological, hematological and bone histological and histomorphometric measurements. Specificity of Al chelation will be assessed by multiple element analysis of selected fluids and tissues. Efficacy and safety results will be correlated to lipophilicity to identify the optimal lipophilicity of the 3-hydroxypyridin-4-ones. The results may identify compounds that warrant testing in humans and will strongly guide the future design and selection of structurally dissimilar compounds as potential Al chelators.