SHORT-TERM ORAL 3-HYDROXYPYRIDIN-4-ONE DOSING INCREASES ALUMINUM EXCRETION AND PARTIALLY REVERSES ALUMINUM-INDUCED TOXICITY IN THE RABBIT INDEPENDENT OF CHELATOR LIPOPHILICITY

The objectives of the present study were to determine the efficacy and toxicity of repeated oral administration of 3-hydroxypyridin-4-one (H P) chelators in a rabbit model of aluminum (Al) accumulation and toxic ity, and the influence of chelator lipophilicity on these effects. Eff icacy was assessed as chelator-induced Al mobilization and excretion a nd reversal of Al accumulation and Al-induced toxicity. Chelator-induc ed toxicity was assessed by multiple measures, Six HPs were given oral ly 12 times over 1 month to Al-loaded rabbits, which had significant e levation of Al in most tissues and evidence of Al-induced nephrotoxici ty, osteomalacia, and anemia, Intravenous desferrioxamine (DFO), the c urrent chelator of choice for the treatment of Al-overload and toxicit y, was included as a positive control. All six HPs and DFO demonstrate d efficacy evidenced by significantly greater urinary and biliary Al e limination after the twelfth dose than seen in saline-treated controls , All of the HPs were more effective than DFO, Chelator-induced urinar y Al excretion accounted for 58-98% of total (urinary plus biliary) Al excretion. Chelator-facilitated Al excretion was nearly complete with in 12 hr, demonstrating a fairly short duration of action in rabbits w ith intact renal function. HP treatments did not consistently affect t issue concentrations of Al or other metals. However, there was a trend toward chelator-induced reduction of Al-induced nephrotoxicity. The i nfluence of HP lipophilicity was limited to a positive correlation bet ween HP Al lipophilicity and biliary Al output and a negative correlat ion between HP and HP Al lipophilicity and reduction of Kupffer cell A l. Little toxicity was evident after repeated oral HP dosing. Adrenal weight increased after treatment with several HPs, There was a decreas e in testes weight after several HPs, which is consistent with an anti proliferative effect, More frequent dosing and/or a longer duration of HP treatment might produce greater reversal of the Al-induced toxicit y and perhaps reveal more adverse effects than seen in this study. The re 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 mos t extensively studied HPs, were the least effective of the HPs examine d, These results encourage the further investigation of other HPs as o ral alternatives to DFO for the treatment of Al accumulation and toxic ity.