197.

197. Yokel RA, Kostenbauder HB. Assessment of potential aluminum chelators in an octanol/aqueous system and in the aluminum-loaded rabbit. Toxicol. Appl. Pharmacol. 1987; 91(2):281-294. (CA) Al solubilizaton from Al borate and its distribution in an octanol/aq. system (Do/w) were detd. in the absence and presence of 12 potential Al chelators. Citrate, N,N1-bis(2-hydroxybenzyl)ethylenediamine-N,N1-diacetic acid (HBED), cyclohexane-1,2-diaminotetraacetic acid (CDTA), diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), desferrioxamine, and ethylenediamine-N,N1-bis(2-dihydroxyphenylacetic acid) (EDDHA) were 55 to >100% efficient in solubilizing equimolar amts. of Al. Tetracycline, EDTA, and 2,3-dihydroxybenzoic acid (DHBA) were <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, resp.). The Do/w of DHBA, desferrioxamine, EDDHA, and HBED were not influenced by Al, but tetracycline became more lipophilic. These compds. were tested for their ability to increase urinary Al excretion in Al-loaded rabbits. Chelators were given orally weekly beginning 2 wk after Al loading. Urine was obtained hourly from 3 h prior to 6 h after chelator administration and analyzed for Al. Fluoride and tetracycline (450 and 4500 mmol/kg) and citrate, NTA, EDTA, CDTA, DTPA, DHBA, HBED, and 1,4-dioxane (150 and 1500 mmol/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 mmol/kg) significantly increased urinary Al excretion. EDDHA and desferrioxamine (150 mmol/kg) were administered by oral, s.c. , and i.v. routes and had comparable potency. The in vitro results may explain some of the in vivo findings. The in vitro methods may be useful to screen out compds. with no chelation potential. EDDHA-like compds. may have potential as alternatives to desferrioxamine in the prevention or treatment of Al accumulation and Al-induced toxicity.

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