Yokel R A, Meurer K A, Hong C B, Dickey K M, Skinner T L, Fredenburg A M
College of Pharmacy, Graduate Center for Toxicology, University of Kentucky, Lexington, USA.
Drug Metab Dispos. 1997 Feb;25(2):182-90.
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 x Al lipophilicity and biliary Al output and a negative correlation between HP and HP x 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.
本研究的目的是确定在铝（Al）蓄积和毒性的兔模型中重复口服3-羟基吡啶-4-酮（HP）螯合剂的疗效和毒性，以及螯合剂亲脂性对这些效应的影响。疗效评估指标为螯合剂诱导的铝动员、排泄以及铝蓄积和铝诱导毒性的逆转。通过多种指标评估螯合剂诱导的毒性。给铝负荷兔在1个月内口服6种HP共12次，这些兔大多数组织中的铝显著升高，并有铝诱导的肾毒性、骨软化症和贫血的证据。静脉注射去铁胺（DFO）作为治疗铝过载和毒性的当前首选螯合剂，作为阳性对照。所有6种HP和DFO均显示出疗效，第12次给药后尿和胆汁中铝的排泄量显著高于生理盐水处理的对照组。所有HP均比DFO更有效。螯合剂诱导的尿铝排泄占总（尿加胆汁）铝排泄量的58-98%。在12小时内，螯合剂促进的铝排泄几乎完成，表明在肾功能正常的兔中作用持续时间相当短。HP治疗并未始终影响组织中铝或其他金属的浓度。然而，存在螯合剂诱导铝诱导肾毒性降低的趋势。HP亲脂性的影响仅限于HP×Al亲脂性与胆汁铝输出之间呈正相关，而HP和HP×Al亲脂性与枯否细胞铝减少之间呈负相关。重复口服HP给药后几乎没有明显毒性。几种HP治疗后肾上腺重量增加。几种HP治疗后睾丸重量下降，这与抗增殖作用一致。更频繁给药和/或更长时间的HP治疗可能会使铝诱导的毒性得到更大程度的逆转，并且可能会揭示比本研究中更多的不良反应。在这项短期研究中没有严重毒性。1,2-二甲基（CP20）和1,2-二乙基（CP94）HP是研究最广泛的HP，在所研究的HP中效果最差。这些结果鼓励进一步研究其他HP，作为DFO的口服替代品用于治疗铝蓄积和毒性。
