Brain regional pharmacokinetics of p-aminosalicylic acid and its N-acetylated metabolite: effectiveness in chelating brain manganese.

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 t(½) of 34 min; the metabolite AcPAS was detected in plasma and eliminated with a t(½) of 147 min. PAS and AcPAS were detected in brain tissues; AcPAS had a much higher tissue concentration and a longer t(½) 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.

HPLC analysis of para-aminosalicylic acid and its metabolite in plasma, cerebrospinal fluid and brain tissues.

Para-aminosalicylic acid (PAS), an approved drug for treatment of tuberculosis, is a promising therapeutic agent for treatment of manganese (Mn)-induced parkinsonian syndromes. Lack of a quantifying method, however, has hindered the clinical evaluation of its efficacy and there upon new drug development. This study was aimed at developing a simple and effective method to quantify PAS and its major metabolite, N-acetyl-para-aminosalicylic acid (AcPAS), in plasma, cerebrospinal fluid (CSF) and tissues. Biological samples underwent one-step protein precipitation. The supernatant was fractionated on a reversed-phase C18 column with a gradient mobile system, followed by on-line fluorescence detection. The lower limits of quantification for both PAS and AcPAS were 50 ng/ml of plasma and 17 ng/g of tissues. The intra-day and inter-day precision values did not exceed 5% and 8%, respectively, in all three matrices. The method was used to quantify PAS and AcPAS in rat plasma and brain following a single iv injection of PAS. Data showed a greater amount of PAS than AcPAS in plasma, while a greater amount of AcPAS than PAS was found in brain tissues. The method has been proven to be sensitive, reproducible, and practically useful for laboratory and clinical investigations of PAS in treatment of Mn Parkinsonism.