AbstractThe prospect of selecting oral α‐ketohydroxypyridine 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 with59Fe have shown that only the 1‐substituted methyl, ethyl, (n)propyl, allyl, cyclopropyl, 2′‐methoxyethyl, 3′‐ethoxypropyl, or 2‐methyl‐ or 2‐ethyl‐ 3‐hydroxypyrid‐4‐one chelators were orally effective in increasing iron (59Fe) excretion by comparison to intraperitoneally administered desferrioxamine at the same dose (250 mg/kg). 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 intraperitoneal routes. In vitro studies using ferritin and haemosiderin have shown that equivalent iron release took place with both groups of chelators irrespective of their in vivo effects. In most cases there was no correlation between the n‐octanol/water partition coefficient (Kpar) and iron removal efficacy but positive correlation between the lipophilicity 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‐one (EL1NEt). The most effective chelator in increasing iron excretion in mice and rabbits was 1‐allyl‐2‐methyl‐3‐hydroxypyrid‐4‐one (L1NAll), and the chelator with the highest safety margin in mice and rats was 1, 2‐dimethyl‐3‐hydroxypyrid‐4‐one (L1). Overall the oral effectiveness in increasing iron excretion by these chelators in animals does not appear to be related to their lipophilicity or their ability to mobilise polynuclear iron in vitro but rather to other properties possibly related to