Comparison of iron chelator efficacy in iron-overloaded Beagle dogs and monkeys (Cebus apella)

Rodents and dogs are frequently used for preclinical toxicologic assessment of candidate iron chelators. Although the iron-clearing profile of a ligand often is known in rodents, and sometimes in primates, such information in dogs is rarely, if ever, available. Because of this, toxicity studies in dogs could be misleading; chelators that may otherwise be suitable for human clinical studies may be abandoned as being unacceptably toxic, simply because, unknown to the investigator, these drugs remove more iron in this species than would have been expected on the basis of iron clearance results in other species. This is a scenario that we encountered during toxicity trials of (S)-β,β-dimethyl-4′-hydroxydesazadesmethyldesferrithiocin in dogs. Thus, we developed an iron-overloaded dog model in which it is possible to evaluate iron-clearing efficiencies of potential therapeutic ligands. Seven deferration agents have been screened in this model, and the results were compared with the iron-clearing efficiency of the same ligands in an iron-loaded Cebus apella monkey model. The data suggest that while the iron-clearing efficiencies of most of the drugs were similar between the two species, there can be profound differences. This is consistent with the idea that caution needs to be exercised when carrying out preclinical toxicity evaluations of a chelator in dogs without first measuring the drug's iron-clearing efficiency in this species.