Abstract
D‐Serine is a co‐agonist of the N‐methyl‐D‐aspartate receptor in glutamate neurotransmission and has been proposed as a potential therapeutic agent for schizophrenia. However, D‐serine also acts as a nephrotoxic substance in rats at high doses. To investigate the pharmacokinetics and toxicokinetics of D‐serine, a method for the stereoselective determination of serine enantiomers in rat plasma was developed using GC‐MS with selected ion monitoring (GC‐MS‐SIM). DL‐[^2^H~3~]Serine was used as an internal standard to account for losses associated with the extraction, derivatization and chromatography. Serine enantiomers were purified by cation‐exchange chromatography using BondElut SCX cartridge and derivatized with HCl in methanol to form methyl ester followed by subsequent N,O‐diacylation with optically active (+)‐α‐methoxy‐α‐trifluoromethylphenylacetyl chloride to form epimeric amide. Quantitation was performed by SIM of the molecular‐related ions of the epimers in the chemical ionization mode. The intra‐ and inter‐day reproducibility of the assay was less than 5% for D‐serine and 3% for L‐serine. The method was successively applied to study the pharmacokinetics of D‐serine in rats. Copyright © 2011 John Wiley & Sons, Ltd.