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 the in vivo aluminum (Al) chelation activity of 3-hydroxypyridin-4-ones (HPs). Chelation activity was evidenced as increased Al elimination in an animal model of Al accumulation and toxicity. The subjects were Al-loaded rabbits. A non-Al-loaded group was included to characterize the rabbit model of Al intoxication. Eight HPs and desferrioxamine (DFO), the drug currently used to treat Al intoxication, were studied. Chelation activity was determined from quantitative biliary and urinary Al excretion and serum Al determinations conducted for 24 hr after DFO or HP intravenous administration, compared with saline. Toxicity was evaluated by observation, blood biochemistry assays, hematological evaluation, 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 chelation, 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 excretion accounted for 78-98% of total Al excretion. Nearly all of the chelator-facilitated Al excretion occurred within 8 hr of dosing. Al chelation efficacy did not correlate with HP or HP Al lipophilicity; however, increasing HP lipophilicity increased the biliary fraction of the excreted Al. There was no evidence for toxicity after HP dosing, other than the previously shown ability of one of the HPs to produce seizures. The greater chelation efficacy of the HPs than DFO provides advantages over DFO. The lack of toxicity after a single dose of all but the most lipophilic HP encourages their further evaluation as orally effective chelators.
Yokel
R A
RA
College of Pharmacy, University of Kentucky, USA.
Meurer
K A
KA
Skinner
T L
TL
Fredenburg
A M
AM
D000535:Aluminum / Q000737:chemistry / Q000493:pharmacokinetics / Q000506:poisoning*; D000818:Animals; D001646:Bile / Q000737:chemistry; D002614:Chelating Agents / Q000737:chemistry*; D003676:Deferoxamine / Q000737:chemistry*; D004195:Disease Models, Animal; D008297:Male; D011728:Pyridones / Q000737:chemistry*; D011817:Rabbits
D002614:Chelating Agents; D011728:Pyridones; D000535:Aluminum; D003676:Deferoxamine