Determination of brain and plasma drug concentrations by liquid chromatography/tandem mass spectrometry

A method is described for the evaluation of drug concentrations in plasma a nd brain from treated rats. The analyte is recovered from plasma or brain h omogenate by liquid-liquid extraction and subsequently analyzed by liquid c hromatography/tandem mass spectrometry (LC/MS/MS), A simple experimental pr otocol renders the procedure valuable for obtaining information rapidly on brain penetration and plasma exposure of specific classes of compounds. Thi s methodology has been applied to evaluate brain penetration with 30 differ ent compounds from the same discovery program. In an attempt to increase th roughput in our screening efforts, mixture dosing was evaluated. Results fr om single compound administration were compared with results following admi nistration of a mixture of four compounds. Preliminary results, with specif ic classes of compounds, show no major differences (ranking order) in brain or plasma concentrations between mixture dosing and single compound admini stration, suggesting that mixture dosing could be applicable to brain penet ration studies in the drug discovery phase. Copyright (C) 2000 John Wiley & Sons, Ltd.