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Research ArticleArticle

Brain Regional Pharmacokinetics of p-Aminosalicylic Acid and Its N-Acetylated Metabolite: Effectiveness in Chelating Brain Manganese

Lan Hong, Wendy Jiang, Hao Pan, Yueming Jiang, Su Zeng and Wei Zheng
Drug Metabolism and Disposition October 2011, 39 (10) 1904-1909; DOI: https://doi.org/10.1124/dmd.111.040915
Lan Hong
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Wendy Jiang
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Hao Pan
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Yueming Jiang
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Su Zeng
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Wei Zheng
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Abstract

para-Aminosalicylic acid (PAS; 4-amino-2-hydroxybenzoic acid), an antituberculosis drug in use since the 1950s, has recently been suggested to be an effective agent for treatment of manganese-induced parkinsonian disorders. However, the neuropharmacokinetics of PAS and its metabolite N-acetyl-para-aminosalicylic acid (AcPAS; N-acetyl-4-amino-2-hydroxybenzoic acid) are unknown. This study was designed to investigate the pharmacokinetics of PAS and its distribution in brain to help better design the dosing regimen for clinical trials. Male Sprague-Dawley rats received single femoral artery injections of PAS (200 mg/kg). Plasma, cerebrospinal fluid, and brain tissues were collected, and PAS and AcPAS concentrations were quantified by high-performance liquid chromatography. After administration, the concentrations of PAS declined rapidly in plasma with an elimination t1/2 of 34 min; the metabolite AcPAS was detected in plasma and eliminated with a t1/2 of 147 min. PAS and AcPAS were detected in brain tissues; AcPAS had a much higher tissue concentration and a longer t1/2 than the parent PAS in most tissues examined. Although both were present in blood or tissues as free, unbound molecules, AcPAS appeared to have a higher tissue affinity than PAS. Taken together, our results suggest that a dosing regimen with continuous intravenous infusion of PAS is necessary to achieve therapeutic levels in targeted brain regions. Furthermore, PAS and AcPAS seem to be effective in reducing manganese levels in brain.

Footnotes

  • This work was supported in part by the National Institutes of Health National Institute of Environmental Health Sciences [Grant R01-ES008146]; the United States Army Medical Research and Materiel Command [Contract W81XWH-05-1-0239]; and the National Major Special Project for Science and Technology Development, Ministry of Science and Technology of China [Grant 2009ZX09304-003].

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.111.040915.

  • ABBREVIATIONS:

    PAS
    4-amino-2-hydroxybenzoic acid
    AcPAS
    N-acetyl-4-amino-2-hydroxybenzoic acid
    AUC0–∞
    area under the concentration-time curve from time zero to infinity
    Cmax
    maximal plasma concentration after dosing
    CSF
    cerebrospinal fluid
    HPLC
    high-performance liquid chromatography
    TEMED
    N,N,N′,N′-tetramethylethylenediamine
    Tmax
    time to reach Cmax.

  • Received May 26, 2011.
  • Accepted July 18, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (10)
Drug Metabolism and Disposition
Vol. 39, Issue 10
1 Oct 2011
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Research ArticleArticle

PHARMACOKINETICS OF PAS AND ACPAS IN RATS

Lan Hong, Wendy Jiang, Hao Pan, Yueming Jiang, Su Zeng and Wei Zheng
Drug Metabolism and Disposition October 1, 2011, 39 (10) 1904-1909; DOI: https://doi.org/10.1124/dmd.111.040915

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Research ArticleArticle

PHARMACOKINETICS OF PAS AND ACPAS IN RATS

Lan Hong, Wendy Jiang, Hao Pan, Yueming Jiang, Su Zeng and Wei Zheng
Drug Metabolism and Disposition October 1, 2011, 39 (10) 1904-1909; DOI: https://doi.org/10.1124/dmd.111.040915
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