PT  - JOURNAL ARTICLE
AU  - Lan Hong
AU  - Wendy Jiang
AU  - Hao Pan
AU  - Yueming Jiang
AU  - Su Zeng
AU  - Wei Zheng
TI  - Brain Regional Pharmacokinetics of p-Aminosalicylic Acid and its N-acetylated Metabolite: In Relation to Their Effectiveness in Chelating Brain Manganese
AID  - 10.1124/dmd.111.040915
DP  - 2011 Jul 18
TA  - Drug Metabolism and Disposition
PG  - dmd.111.040915
4099  - http://dmd.aspetjournals.org/content/early/2011/07/18/dmd.111.040915.short
4100  - http://dmd.aspetjournals.org/content/early/2011/07/18/dmd.111.040915.full
AB  - Para-aminosalicylic acid (PAS), an anti-tuberculosis drug in use since the 1950s, has recently been suggested to be an effective agent for treatment of manganese (Mn)-induced parkinsonian disorders. However, the neuro-pharmacokinetics of PAS and its metabolite N-acetyl-para-aminosalicylic acid (AcPAS) 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 (200mg/kg). Plasma, cerebrospinal fluid (CSF), and brain tissues were collected, and PAS and AcPAS concentrations were quantified by HPLC. Following 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. Both 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. While 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 iv infusion of PAS is necessary to achieve therapeutic levels in targeted brain regions. Furthermore, both PAS and AcPAS seem to be effective in reducing Mn levels in brain.