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N-acetyl-]-(p-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquiiioline derivative (PS3Ac) has been determined in brain tissues by high performance liquid chromatography (HPLC) coupled with a diode array detection. In a previous paper we presented a validation method for detecting PS3Ac and its metabolites in plasma samples after intraperitoneal administration to Wistar rats. In the present paper, we report the results of the determination of PS3Ac and its N-deacetyl (PS3) and O-demethyl (PS3OH) metabolites, in the brain after extraction based on a polymeric matrix with a high hydrophilic-lipophilic balance, using Oasis cartridges. The chromatographic separation was performed in an octadecylsilica stationary phase at 25 degrees C using a mixture of 10 mM potassium dihydrogen orthophosphate (pH 2.24) and acetonitrile in ratio of 30:70 (v/v) as mobile phase, with a flow rate of 0.8 ml/min. The method exhibited a large linear range from 0.05 to 2 mu g/ml for all studied compounds (n = 6). In the within-day assay (n = 4), the accuracy ranged from 87.5% determined with 0.05 mu g/ml of PS3 to 110.1% determined with 0.2 mu g/ml of PS3OH. In the between-day assay the coefficient of variation ranged from 2.4 determined with 0.05 mu g/ml of PS3 to 9.7 determined with 0.2 mu g/ml of PS3OH. The extraction efficiency ranged from 77.8% for PS3OH at 0.2 mu g/ml to 94.3 for PS3Ac at 0.5 mu g/ml. The limit of detection for all the tetrahydroisoquinoline derivatives ranged around 50 mu g/ml. The method proved to be highly sensitive and specific to determinate PS3Ac and its metabolites and has been successfully applied to value their concentrations in brain inatrix over the time. (c) 2006 Elsevier B.V. All rights reserved.