title: Simultaneous Determination of Valproic Acid and Its Major Metabolites by UHPLC-MS/MS in Chinese Patients: Application to Therapeutic Drug Monitoring.
abstract: A specific and sensitive Ultra-high Performance Liquid Chromatography-tandem Mass spectrometry (UHPLC-MS/MS) method was developed for the simultaneous determination of the concentrations of valproic acid (VPA) and its clinically relevant metabolites (4-ene-VPA, 2,4-diene-VPA and 2-ene-VPA) in human serum. After solid-phase extraction, VPA, its metabolites and the internal standard were subjected to chromatographic separation by gradient elution of acetonitrile and 10 mM ammonium acetate as mobile phase at a flow rate of 0.6 mL/min on an EC-C18 column. The method was validated over the concentration ranges of 1-200 μg/mL for VPA, 0.5-10 μg/mL for 2-ene-VPA, 10-500 ng/mL for 4-ene-VPA and 25-500 ng/mL for 2,4-diene-VPA. The inter-day and intra-day accuracy and precision were within the acceptable limits of <15 %. The recoveries and matrix effects met the requirement for the analysis of biological samples. No obvious degradation was observed under various storage conditions including room temperature for 12 h, three freeze-thaw cycles and -80°C for 1 month. The assay method was successfully applied to monitor the concentration of VPA and its three metabolites in epileptic patients. The UHPLC-MS/MS method demonstrated a good analytical performance essential for therapeutic drug monitoring, which would potentially lead to clinically relevant improvements in VPA dosage and patient management.
authors.affiliation: Department of Pharmacy, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang 110004, Liaoning Province, P.R. China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Pharmacy, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang 110004, Liaoning Province, P.R. China.
authors.forename: Ti
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang 110004, Liaoning Province, P.R. China.
authors.forename: Guofei
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Pharmacy, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang 110004, Liaoning Province, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Qiu
authors.affiliation: Department of Pharmacy, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang 110004, Liaoning Province, P.R. China.
authors.forename: Yaxin
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Pharmacy, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang 110004, Liaoning Province, P.R. China.
authors.forename: Limei
authors.initials: L
authors.lastname: Zhao
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D002681:China; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D016903:Drug Monitoring / Q000379:methods*; D004827:Epilepsy / Q000188:drug therapy; D006801:Humans; D007223:Infant; D057230:Limit of Detection; D016014:Linear Models; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry / Q000379:methods*; D014635:Valproic Acid / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D014635:Valproic Acid