Abstract: Objective To establish and validate an LC-MS/MS method for the determination of sodium valproate in human serum, and apply this method to clinical therapeutic drug monitoring (TDM). Methods Cyclohexane carboxylic acid was used as the internal standard (IS). After protein precipitation with acetonitrile, the determination was performed on a triple quadrupole mass spectrometer that used the ESI technique and operated in the multiple reaction monitoring and negative ion mode. The analyte and IS were separated on a Thermo Hypersil BDS C₁₈ column (10×4.6 mm) with a mobile phase composed of 0.1% formic acid-methanol (15∶85) at a flow rate of 0.4 mL·min^-1. The column temperature was set at 30℃. Results The linear range of sodium valproate was 5~120 μg·mL^-1. The limit of quantification was 5 μg·mL^-1. The RSD of accuracy and precision (within-run and between-runs) was less than 15%. The recoveries were within ±15% of the labeled values. The variation coefficient of the internal normalized matrix factor of the serum matrix was less than 15%. The samples were found to be stable when stored at 2~8℃ and -40℃. Approximately 40% of the patients in this study whose serum concentration of sodium valproate were out of the therapeutic ranges. Conclusion The established method has a high specificity and sensitivity, and the accuracy and precision meet the acceptance criteria of bioanalytical methods. The stability and dilution are acceptable. Thus this method could be used for clinical TDM and pharmacokinetic research for determination of VPA in human serum.

Key words: sodium valproate, LC-MS/MS, drug concentrations of serum