The Ability of Tolfenamic Acid to Penetrate the Brain: A Model for Testing the Brain Disposition of Candidate Alzheimer's Drugs Using Multiple Platforms

Evidence from our laboratory suggests that tolfenamic acid has a potential for slowing the progression of Alzheimer's disease (AD) through lowering cortical levels of the β-amyloid precursor protein (APP) and its pathogenic amyloid beta (Aβ) intermediates [1]. In this study, we examined the ability of tolfenamic acid to cross the blood brain barrier (BBB) by predicting its logBB and logPS values, the indexes of BBB permeability, using computational models. We also determined, via in vitro methods, the brain penetration capacity factor [(KIAM/MW4)x1010] using phosphatidylcholine column chromatography. The obtained logBB, logPS and (KIAM/MW4)x1010 values predicted that tolfenamic acid can passively transfer into the central nervous system (CNS). These results were validated in vivo using LC-MS analysis after administration of tolfenamic acid intravenously to guinea pigs and mice. The present study provides the first evidence of the ability of tolfenamic acid to cross the BBB and offers a comparative analysis of approaches used to predict the ability of compounds to penetrate into the brain.