TY - JOUR

T1 - Retrospective analysis for valproate screening targets with liquid chromatography-high resolution mass spectrometry with positive electrospray ionization

T2 - An omics-based approach

AU - Mollerup, Christian Brinch

AU - Rasmussen, Brian Schou

AU - Johansen, Sys Stybe

AU - Mardal, Marie

AU - Linnet, Kristian

AU - Dalsgaard, Petur Weihe

N1 - © 2018 John Wiley & Sons, Ltd.

PY - 2019/5

Y1 - 2019/5

N2 - Liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) is an important analytical tool in the systematic toxicological analysis performed in forensic toxicology. However, some important compounds, such as the antiepileptic drug valproate (valproic acid; VPA), cannot be directly detected with positive electrospray ionization (ESI+ ) due to poor ionization. Here we demonstrate an omics-based retrospective analysis for the identification of indirect screening targets for VPA in whole blood with LC-ESI+ -HRMS. Analysis was performed utilizing data acquired across four years from LC-ESI+ -HRMS, with VPA results from a quantitative LC-MS/MS method. The combined data with VPA results were split into an exploration set (n = 68; 28% positive) and a test set (n = 37; 32% positive). Eight indirect targets for VPA were identified in the exploration set. The evaluation of these targets was confirmed with retrospective target analysis of the test set. Using a combination of two out of the eight indirect targets, we attained a sensitivity of 92% (n = 12; VPA concentration range: 4.4-29.7 mg/kg) and 100% specificity (n = 25) for VPA with LC-ESI+ -HRMS. VPA screening targets were identified with retrospective data analysis and could be appended to the existing screening procedure. A sensitive and specific screening with LC-ESI+ -HRMS was achieved with targets corresponding to the sodium adducts of C7 H14 O3 and C8 H14 O3 . Three chromatographic resolved isomer peaks were observed for the latter, and the consistently most intense peak was tentatively identified as 3-hydroxy-4-en-VPA.

AB - Liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) is an important analytical tool in the systematic toxicological analysis performed in forensic toxicology. However, some important compounds, such as the antiepileptic drug valproate (valproic acid; VPA), cannot be directly detected with positive electrospray ionization (ESI+ ) due to poor ionization. Here we demonstrate an omics-based retrospective analysis for the identification of indirect screening targets for VPA in whole blood with LC-ESI+ -HRMS. Analysis was performed utilizing data acquired across four years from LC-ESI+ -HRMS, with VPA results from a quantitative LC-MS/MS method. The combined data with VPA results were split into an exploration set (n = 68; 28% positive) and a test set (n = 37; 32% positive). Eight indirect targets for VPA were identified in the exploration set. The evaluation of these targets was confirmed with retrospective target analysis of the test set. Using a combination of two out of the eight indirect targets, we attained a sensitivity of 92% (n = 12; VPA concentration range: 4.4-29.7 mg/kg) and 100% specificity (n = 25) for VPA with LC-ESI+ -HRMS. VPA screening targets were identified with retrospective data analysis and could be appended to the existing screening procedure. A sensitive and specific screening with LC-ESI+ -HRMS was achieved with targets corresponding to the sodium adducts of C7 H14 O3 and C8 H14 O3 . Three chromatographic resolved isomer peaks were observed for the latter, and the consistently most intense peak was tentatively identified as 3-hydroxy-4-en-VPA.

KW - biomarker

KW - forensic toxicology screening

KW - indirect screening

KW - retrospective analysis

KW - untargeted high-resolution mass spectrometry screening

U2 - 10.1002/dta.2543

DO - 10.1002/dta.2543

M3 - Journal article

C2 - 30426701

VL - 11

SP - 730

EP - 738

JO - Drug Testing and Analysis

JF - Drug Testing and Analysis

SN - 1942-7603

IS - 5

ER -