Biological models for studying iron chelating drugs.
Experimental models for studying the biological effects of iron chelators range from in vitro cell cultures to in vivo models in a variety of animals. Apart from screening for chelating efficacy, such models have been useful in providing information on the pharmacology of desferrioxamine and a number of other, orally effective iron chelators; in the identification of the biological source of iron mobilized by such chelators; in defining optimal methods of drug delivery; in providing evidence for the ability of iron chelators to prevent or reverse iron toxicity; and in exploring the potential usefulness of iron chelating therapy in conditions unrelated to iron overload, where iron may fulfil a central role in the pathogenesis of disease. Although cell cultures are inexpensive and permit the rapid screening of large numbers of new chelating compounds, they may overlook alternative sources of chelatable iron, pro-drugs, and orally effective compounds. In vivo models provide information on drug toxicity, allow comparison of oral versus parenteral efficacy, routes of excretion of chelated iron, monitoring of selective interaction with various iron pools, and promotion of the excretion of various trace metals. Although iron metabolism in large animals such as dogs and monkeys closely resembles that of humans, small animals such as mice and rats are usually preferred because of their low cost and ease of handling. Thorough knowledge of the pharmacology of iron chelators is a prerequisite for their successful therapeutic application. Interaction with a rapidly exchanging, intracellular, low molecular weight chelatable iron pool requires a steady supply of a drug capable of penetrating the relevant effector cells. The high effectiveness of continuous desferrioxamine infusion illustrates this point and underlines the need for developing new orally effective iron chelators which, by virtue of their slower absorption, would be more suitable for providing a continuous supply of circulating drug.
Hershko
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D000818:Animals; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D007501:Iron / Q000633:toxicity; D007502:Iron Chelating Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008954:Models, Biological
D007502:Iron Chelating Agents; D007501:Iron; D003676:Deferoxamine