Selection of a new generation of orally active α-ketohydroxypyridine iron chelators intended for use in the treatment of iron overload
✍ Scribed by G. J. Kontoghiorghes; J. Barr; P. Nortey; L. Sheppard
- Publisher
- John Wiley and Sons
- Year
- 1993
- Tongue
- English
- Weight
- 909 KB
- Volume
- 42
- Category
- Article
- ISSN
- 0361-8609
No coin nor oath required. For personal study only.
✦ Synopsis
The prospect of selecting oral a-ketohydroxypyrldine chelators Intended for clinical use in iron overload has been examined using several animal models of efficacy and toxicity. Studies using iron dextran-loaded mice labelled with 50Fe have shown that only the 1-substituted methyl, ethyl, (n)propyl, allyl, cyclopropyl, 2'-methoxyethyl, S'ethoxypropyl, or 2-methyl-or 2ethyl-3-hydroxypyrid-hone chelators were orally effective In increasing iron ("Fe) excretion by comparison to intraperitoneally administered desferrloxm i n e at the same dose (250 mglkg). in contrast, chelators containing -H, mono-or dihydroxyalkyl and diethoxyethyl 1-substituents caused very little or no Increase in Iron (59Fe) excretion by the oral or lntraperitoneal routes. In vitro studies using ferrltin and haemosiderln have shown that equivalent iron release took place with both groups of chelators irrespective of their in vlvo effects. In most cases there was no correlation between the n-octanol/water partition coefficient (KPJ and iron removal efficacy but positive correlation between the lipophlllcity and acute or subacute toxicity of these chelators in rats. The most toxic chelator in the chronic toxicity studies in rats was the lipophilic 1,2-diethyl-3-hydroxypyrid-4-0ne (EL1 NEt). The most effective chelator in increasing iron excretion in mice and rabbits was l-allyl-2-methyl-3-hydroxypyrid-4-one (LlNAII), and the chelator with the highest safety margin In mice and rats was 1,2-dimethyl-3-hydroxypyrid4-one (Ll). Overall the oral effectiveness In Increasing Iron excretion by these chelators In animals does not appear to be related to their lipophiliclty or their ability to mobilise polynuclear iron in vltro but rather to other properties possibly related to their rate of biotransformation and excretion.