Development of a high-throughput method for the determination of pharmacological levels of plasma D-serine

D-Serine administration has been shown to be effective for the treatment of schizophrenia symptoms. However, D-serine must be administered at high doses to observe clinical effects. This is due in large part to D-serine undergoing oxidation by D-amino acid oxidase (DAAO) before it reaches the brain. Consequently, coadministration of D-serine with a DAAO inhibitor has been suggested as a way to lower the dose of D-serine required to treat schizophrenia. During the characterization of DAAO inhibitors as potential drugs, inhibitors are evaluated in rodents for their ability to increase plasma D-serine levels after oral coadministration. Current high-performance liquid chromatography (HPLC)-based methodologies to measure D-serine in plasma are time-consuming and are not amenable to concomitant analysis of multiple samples. We report the characterization of a 96-well format assay to monitor D-serine in plasma that greatly expedites analysis time. The assay involves the use of strong cation exchange solid phase extraction (SPE) to isolate D-serine from plasma followed by quantitation of D-serine using the DAAO-catalyzed reaction. Plasma D-serine determination using this assay could also be used as pharmacodynamic marker and as biomarker. (C) 2011 Elsevier Inc. All rights reserved.