title: Determination of brain and plasma drug concentrations by liquid chromatography/tandem mass spectrometry.
abstract: A method is described for the evaluation of drug concentrations in plasma and brain from treated rats. The analyte is recovered from plasma or brain homogenate by liquid-liquid extraction and subsequently analyzed by liquid chromatography/tandem mass spectrometry (LC/MS/MS). A simple experimental protocol renders the procedure valuable for obtaining information rapidly on brain penetration and plasma exposure of specific classes of compounds. This methodology has been applied to evaluate brain penetration with 30 different compounds from the same discovery program. In an attempt to increase throughput in our screening efforts, mixture dosing was evaluated. Results from single compound administration were compared with results following administration of a mixture of four compounds. Preliminary results, with specific classes of compounds, show no major differences (ranking order) in brain or plasma concentrations between mixture dosing and single compound administration, suggesting that mixture dosing could be applicable to brain penetration studies in the drug discovery phase.
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Tamvakopoulos
authors.forename: L F
authors.initials: LF
authors.lastname: Colwell
authors.forename: K
authors.initials: K
authors.lastname: Barakat
authors.forename: J
authors.initials: J
authors.lastname: Fenyk-Melody
authors.forename: P R
authors.initials: PR
authors.lastname: Griffin
authors.forename: R
authors.initials: R
authors.lastname: Nargund
authors.forename: B
authors.initials: B
authors.lastname: Palucki
authors.forename: I
authors.initials: I
authors.lastname: Sebhat
authors.forename: X
authors.initials: X
authors.lastname: Shen
authors.forename: R A
authors.initials: RA
authors.lastname: Stearns
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001923:Brain Chemistry; D002851:Chromatography, High Pressure Liquid; D008297:Male; D013058:Mass Spectrometry; D004364:Pharmaceutical Preparations / Q000032:analysis*; D010599:Pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012015:Reference Standards
chemical_list: D004364:Pharmaceutical Preparations