Evaluation of new iron chelators for clinical use.
Evaluation of new chelators for clinical use is limited by the availability of models which will predict the therapeutic safety margin of chelators in iron-overloaded humans such as those with thalassaemia major. Animal models show significant differences with respect to the relative toxicity of different chelators compared with human. These differences can be ascribed to several factors: differences in iron metabolism between different species, human metabolism being significantly more conservative than in rodents or nonhuman primates; differences in drug metabolism between different species which are often difficult to predict from first principles, and difficulties in obtaining iron-overloaded models that are truly representative of transfusional iron overload clinically. These differences have been highlighted by clinical studies on hydroxypyridinone iron chelators such as 1,2-dimethyl-3-hydroxypyridin-4-one (L1, CP20, deferiprone) and 1,2-diethyl-3-hydroxypyridin-4-one (CP94). New tissue culture approaches towards understanding the mechanisms of neutropenia, cytostasis and apoptosis induced by chelators as well as the relative rates of inhibition of non-haem-iron-containing enzymes such as ribonucleotide reductase are predicted to identify chelators with a higher therapeutic safety margin.
Porter
J B
JB
Department of Haematology, University College London, UK.
D000818:Animals; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006486:Hemosiderosis / Q000188:drug therapy; D006801:Humans; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D013045:Species Specificity
D007502:Iron Chelating Agents; D007501:Iron