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.
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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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