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Research ArticleArticle

Short-Term Oral 3-Hydroxypyridin-4-one Dosing Increases Aluminum Excretion and Partially Reverses Aluminum-Induced Toxicity in the Rabbit Independent of Chelator Lipophilicity

Robert A. Yokel, Kathryn A. Meurer, Chuen B. Hong, Kenneth M. Dickey, Thomas L. Skinner and Andrea M. Fredenburg
Drug Metabolism and Disposition February 1997, 25 (2) 182-190;
Robert A. Yokel
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Kathryn A. Meurer
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Chuen B. Hong
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Kenneth M. Dickey
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Thomas L. Skinner
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Andrea M. Fredenburg
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Abstract

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 · Al lipophilicity and biliary Al output and a negative correlation between HP and HP · 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.

Footnotes

  • Send reprint requests to: Dr. Robert A. Yokel, Pharmacy Building, University of Kentucky Medical Center, Lexington, KY 40536-0082.

  • This study was supported by the National Institutes of Health Grant ES RO1 4640 (to R.A.Y.) and by Grant 5 T32 ESO7265-04 (to A.M.F.).

  • ↵2 R. A. Yokel and J. P. O’Callaghan, submitted for publication.

  • ↵3 H. P. Schnebli, personal communication.

  • Abbreviations used are::
    Al
    aluminum
    DFO
    desferrioxamine
    HP
    3-hydroxypyridin-4-one
    Do/a
    partition coefficient
    CP20
    1,2-dimethyl 3-hydroxypyridin-4-one
    iv
    intravenous
    Na
    sodium
    GFAP
    glial fibrillary acidic protein
    ETAAS
    electrothermal atomic absorption spectroscopy
    CSF
    cerebrospinal fluid
    Mg
    magnesium
    Ca
    calcium
    Cu
    copper
    Fe
    iron
    Ni
    nickel
    Zn
    zinc
    CP40
    1-[ethan-1′-ol]-2-methyl-3-hydroxypyridin-4-one
    CP24
    1-n-butyl-2-methyl-3-hydroxypyridin-4-one
    CP52
    1-[3′-ethoxypropyl]-2-methyl-3-hydroxypyridin-4-one
    CP93
    1-methyl-2-ethyl-3-hydroxypyridin-4-one
    CP94
    1,2-diethyl-3-hydroxypyridin-4-one
    • Received July 11, 1996.
    • Accepted October 31, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 2
1 Feb 1997
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Research ArticleArticle

Short-Term Oral 3-Hydroxypyridin-4-one Dosing Increases Aluminum Excretion and Partially Reverses Aluminum-Induced Toxicity in the Rabbit Independent of Chelator Lipophilicity

Robert A. Yokel, Kathryn A. Meurer, Chuen B. Hong, Kenneth M. Dickey, Thomas L. Skinner and Andrea M. Fredenburg
Drug Metabolism and Disposition February 1, 1997, 25 (2) 182-190;

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Research ArticleArticle

Short-Term Oral 3-Hydroxypyridin-4-one Dosing Increases Aluminum Excretion and Partially Reverses Aluminum-Induced Toxicity in the Rabbit Independent of Chelator Lipophilicity

Robert A. Yokel, Kathryn A. Meurer, Chuen B. Hong, Kenneth M. Dickey, Thomas L. Skinner and Andrea M. Fredenburg
Drug Metabolism and Disposition February 1, 1997, 25 (2) 182-190;
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