Selection of hydroxypyridin-4-ones for the treatment of iron overload using in vitro and in vivo models.
The hydroxypyridin-4-one group of iron chelators show promise as potential compounds for the treatment of iron overload by the oral route. In the search for the compounds best suited for long term clinical use, a balance has to be struck between the desire to mobilise the maximum amount of iron and the wish to minimise the potential toxicity of such compounds. In this article we review the approach we have used to evaluate which of the hydroxypyridinones have the properties best suited for further development prior to clinical trials in man. The diversity of a number of closely related compounds substituted on the ring nitrogen have allowed us to study the properties of chelators responsible for cellular mobilisation of iron(III), as well as those which may contribute to their toxicity. The primary hepatocyte culture model has facilitated the investigation of the contribution of their iron binding constant, as well as the critical importance of their relative lipid solubility to both cellular iron mobilisation and toxicity. Similarly studies in mice have confirmed that the factors affecting cellular iron release also control iron excretion in whole animals. Further we have demonstrated that the acute toxicity of this group of compounds is closely linked to the size of the available iron pool.(ABSTRACT TRUNCATED AT 250 WORDS)
Huehns
E R
ER
University College London.
Porter
J B
JB
Hider
R C
RC
D000818:Animals; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D007501:Iron / Q000633:toxicity*; D007502:Iron Chelating Agents / Q000627:therapeutic use* / Q000633:toxicity; D008099:Liver / Q000166:cytology / Q000187:drug effects; D051379:Mice; D011728:Pyridones / Q000627:therapeutic use* / Q000633:toxicity
D007502:Iron Chelating Agents; D011728:Pyridones; D007501:Iron