Assessment of potential aluminum chelators in an octanol/aqueous system and in the aluminum-loaded rabbit.
Aluminum (Al) solubilization from Al borate and its distribution in an octanol/aqueous system (Do/w) were determined in the absence and presence of 12 potential Al chelators. Citrate, N,N'-bis-(2-hydroxybenzyl)ethylenediamine- N,N'-diacetic acid (HBED), cyclohexane-1,2-diaminotetraacetic acid (CDTA), diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), desferrioxamine, and ethylenediamine-N,N'-bis(2-dihydroxyphenylacetic acid) (EDDHA) were 55 to over 100% efficient in solubilizing equimolar amounts of Al. Tetracycline, EDTA, and 2,3-dihydroxybenzoic acid (DHBA) were less than 20% efficient. 1,4-Dioxane and fluoride were ineffective. The Do/w of Al averaged 0.005. The Do/w of the Al.chelator complex was generally less than that of Al, except for HBED and tetracycline (0.04 and 0.96, respectively). The Do/w of DHBA, desferrioxamine, EDDHA, and HBED were not influenced by Al, but tetracycline became more lipophilic. These compounds were tested for their ability to increase urinary Al excretion in Al-loaded rabbits. Chelators were given po weekly beginning 2 weeks after Al loading. Urine was obtained hourly from 3 hr prior to 6 hr after chelator administration and analyzed for Al. Fluoride and tetracycline (450 and 4500 mumol/kg) and citrate, NTA, EDTA, CDTA, DTPA, DHBA, HBED, and 1,4-dioxane (150 and 1500 mumol/kg) were ineffective. Following HBED administration, some of the Al-loaded rabbits died, presumably due to redistribution of Al within the rabbit. Following DTPA administration, some of the Al-loaded rabbits died, presumably due to DTPA. Oral EDDHA (1500 mumol/kg) significantly increased urinary Al excretion. EDDHA and desferrioxamine (150 mumol/kg) were administered by po, sc, and iv routes and were found to have comparable potency. The in vitro results may explain some of the in vivo findings. The in vitro methods may be useful to screen out compounds with no chelation potential. EDDHA-like compounds may have potential as alternatives to desferrioxamine in the prevention or treatment of Al accumulation and Al-induced toxicity.
Yokel
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RA
College of Pharmacy, University of Kentucky, Lexington 40536-0082.
Kostenbauder
H B
HB
D000535:Aluminum / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D002264:Carboxylic Acids; D002614:Chelating Agents / Q000494:pharmacology; D003676:Deferoxamine; D004146:Dioxanes; D008954:Models, Biological; D000442:Octanols; D011817:Rabbits; D013329:Structure-Activity Relationship; D013752:Tetracycline; D013816:Thermodynamics; D014867:Water
D002264:Carboxylic Acids; D002614:Chelating Agents; D004146:Dioxanes; D000442:Octanols; D014867:Water; D000535:Aluminum; D013752:Tetracycline; D003676:Deferoxamine; C025223:1,4-dioxane