Relative Oral Efficacy and Acute Toxicity of Hydroxypyridin-4-One Iron Chelators in Mice

The relationship between the oral efficacy and the acute toxicity of hydroxypyridin4one iron chelators has been investigated to clarify structure-function relationships of these compounds in vivo and to identify compounds with the maximum therapeutic safety margin. By comparing “Fe excretion following oral or intraperitoneal administration of increasing doses of each chelator to iron-overloaded mice, the most effective compounds have been identified. These have partition coefficients (Kpart) above 0.3 in the iron-free form with a trend of increasing oral efficacy with increasing Kpart values (r = .6). However, this is achieved at a cost of increasing acute toxicity, as shown by a linear correlation between ”Fe excretion increase per unit dose