Reduced CNS exposure of memantine in a triple transgenic mouse model of Alzheimer's disease assessed using a novel LC–MS technique

Abstract

A sensitive and robust LC–MS method for quantifying memantine (MEM) concentrations in mouse brain homogenate and perfusate was developed and validated. The developed LC–MS method exhibited good linearity between response and MEM concentrations in both perfusate and brain homogenate (r2=0.98–0.99) with mean accuracy and precision values of 105.6% and 7.7% (for perfusate) and 99.0% and 9.5% (for brain homogenate). This assay was then applied to determine the impact of reported blood–brain barrier (BBB) alterations in Alzheimer's disease (AD) on the CNS exposure of the anti-AD drug, MEM. The brain uptake of MEM was measured in 12–13 and 17–19 month old wild-type (WT) and triple transgenic (3×Tg) AD mice using the developed LC–MS assay and a transcardiac perfusion technique. The transcardiac perfusion technique was validated in our laboratory with marker compounds (each representing different mechanisms of transport across the BBB) to ascertain that the physical and functional properties of the BBB were maintained using this technique. While the brain uptake of MEM was not significantly different between WT and 3×Tg mice at 12–13 months, MEM brain uptake was significantly (p<0.05) decreased by 43% in 17–19 month old 3×Tg mice relative to WT mice. Using this novel LC–MS technique, the CNS exposure of a therapeutically-relevant drug, MEM, has been shown to be decreased in AD, implying a need to assess the impact of this disorder on the brain uptake of other therapeutically-relevant compounds.