THE 3-HYDROXYPYRIDIN-4-ONES MORE EFFECTIVELY CHELATE ALUMINUM IN A RABBIT MODEL OF ALUMINUM INTOXICATION THAN DOES DESFERRIOXAMINE

This study was conducted to assess the influence of lipophilicity on t he in vivo aluminum (Al) chelation activity of 3-hydroxypyridin-4-ones (HPs). Chelation activity was evidenced as increased Al elimination i n an animal model of Al accumulation and toxicity, The subjects were A l-loaded rabbits. A non-Al-loaded group was included to characterize t he rabbit model of Al intoxication, Eight HPs and desferrioxamine (DFO ), the drug currently used to treat Al intoxication, were studied, Che lation activity was determined from quantitative biliary and urinary A l excretion and serum Al determinations conducted for 24 hr after DFO or HP intravenous administration, compared with saline, Toxicity was e valuated by observation, blood biochemistry assays, hematological eval uation, gross necropsy, and histopathological assessment of the liver, Al loading produced nephrotoxicity, hepatotoxicity, and anemia. Each of the chelators mobilized Al into serum, The efficiency of Al chelati on, calculated from 24-hr biliary plus urinary Al output, ranged from 2.8 to 11.7% for the HPs, compared with 2.1% for DFO, Urinary Al excre tion accounted for 78-98% of total Al excretion, Nearly all of the che lator-facilitated Al excretion occurred within 8 hr of dosing, Al chel ation efficacy did not correlate with HP or HP . Al lipophilicity; how ever, increasing HP lipophilicity increased the biliary fraction of th e excreted Al, There was no evidence for toxicity after HP dosing, oth er than the previously shown ability of one of the HPs to produce seiz ures, The greater chelation efficacy of the HPs than DFO provides adva ntages over DFO, The lack of toxicity after a single dose of all but t he most lipophilic HP encourages their further evaluation as orally ef fective chelators.