Abstract

The objectives of the present study were to determine the efficacy and toxicity of repeated oral administration of 3-hydroxypyridin-4-one (HP) chelators in a rabbit model of aluminum (Al) accumulation and toxicity, and the influence of chelator lipophilicity on these effects. Efficacy was assessed as chelator-induced Al mobilization and excretion and reversal of Al accumulation and Al-induced toxicity. Chelator-induced toxicity was assessed by multiple measures. Six HPs were given orally 12 times over 1 month to Al-loaded rabbits, which had significant elevation of Al in most tissues and evidence of Al-induced nephrotoxicity, osteomalacia, and anemia. Intravenous desferrioxamine (DFO), the current chelator of choice for the treatment of Al-overload and toxicity, was included as a positive control.

All six HPs and DFO demonstrated efficacy evidenced by significantly greater urinary and biliary Al elimination after the twelfth dose than seen in saline-treated controls. All of the HPs were more effective than DFO. Chelator-induced urinary Al excretion accounted for 58–98% of total (urinary plus biliary) Al excretion. Chelator-facilitated Al excretion was nearly complete within 12 hr, demonstrating a fairly short duration of action in rabbits with intact renal function.

HP treatments did not consistently affect tissue concentrations of Al or other metals. However, there was a trend toward chelator-induced reduction of Al-induced nephrotoxicity. The influence of HP lipophilicity was limited to a positive correlation between HP · Al lipophilicity and biliary Al output and a negative correlation between HP and HP · Al lipophilicity and reduction of Kupffer cell Al.

Little toxicity was evident after repeated oral HP dosing. Adrenal weight increased after treatment with several HPs. There was a decrease in testes weight after several HPs, which is consistent with an antiproliferative effect. More frequent dosing and/or a longer duration of HP treatment might produce greater reversal of the Al-induced toxicity and perhaps reveal more adverse effects than seen in this study.

There was a lack of profound toxicity during this short-term study. The 1,2-dimethyl (CP20) and 1,2-diethyl (CP94) HPs, which have been the most extensively studied HPs, were the least effective of the HPs examined. These results encourage the further investigation of other HPs as oral alternatives to DFO for the treatment of Al accumulation and toxicity.