Retrospective analysis for valproate screening targets with liquid chromatography–high resolution mass spectrometry with positive electrospray ionization: An omics‐based approach

Mollerup, Christian Brinch; Rasmussen, Brian Schou; Johansen, Sys Stybe; Mardal, Marie; Línnet, Kristían; Dalsgaard, Petur Weihe

doi:10.1002/dta.2543

Cited by 25 publications

(35 citation statements)

References 36 publications

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“…The retrospective omics‐based workflow consists of three steps and has previously been described by Mollerup et al Step 1 identifies all peaks in the positive samples and groups them with a mean‐shift algorithm using a bandwidth of 3 mDa and 0.1minute retention time. Peak clusters that consist of a peak found in at least 50% of the positive samples were selected as possible targets for phenobarbital.…”

Section: Methodsmentioning

confidence: 99%

“…Thus, if a compound has been assumed not to be directly detectable in ESI + , one can try to look for peaks that are related to the given compound by comparing the peak lists from positive samples to the peak lists from negative samples, resulting in a group of peaks that exclusively appear in the positive samples. This approach has recently been used to tentatively identify valproic acid in ESI + which was assumed only to be detectable in ESI − …”

Section: Introductionmentioning

confidence: 99%

“…This approach has recently been used to tentatively identify valproic acid in ESI + which was assumed only to be detectable in ESI − . 9 The aim of this work was to identify peaks that enable indirect identification of phenobarbital in LC−HRMS ESI + using retrospective analysis of screening data from the past four years.…”

Section: Introductionmentioning

confidence: 99%

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Identification of phenobarbital and other barbiturates in forensic drug screening using positive electrospray ionization liquid chromatography−high resolution mass spectrometry

Høj

Mollerup

Rasmussen

et al. 2019

Drug Testing and Analysis

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Comprehensive drug‐screening performed by liquid chromatography−high resolution mass spectrometry (LC−HRMS) enables identification of hundreds to thousands of drug compounds in a single analysis. Forensic drug screening is generally performed with positive electrospray ionization (ESI+), targeting basic drugs; however, a few toxicologically important drugs such as barbiturates, may require analysis by negative ESI. In this work, screening targets for barbiturates were determined using our LC−HRMS screening with ESI+. For several years, our forensic whole blood samples have been analyzed using the LC−HRMS−ESI+ screening in parallel with a multi‐target LC–MS/MS−ESI− method. From 2014 to 2018, 23 samples were positive for phenobarbital (0.5−81 mg/kg). Retrospective data analysis of 4816 blood samples (15 positive) revealed several potential screening targets for phenobarbital. The targets were tentatively identified by exact mass and isotopic pattern as uncommon adducts of phenobarbital and as a decomposition product of phenobarbital N‐glucoside (C17H24N2O7). Analysis of a test set containing eight positive (0.5–65 mg/kg phenobarbital) and 31 negative samples supported the use of the observed target m/z 323.0614 at 5.14 minutes, corresponding to the [M + HCOONa+Na]+ adduct of phenobarbital. The [M + HCOONa+Na]+ adduct was confirmed as a screening target for common barbiturates, by analysis of barbiturate reference standards in ESI+/ESI−. The [M + HCOONa+Na]+ adduct allowed retrospective analysis with 91% sensitivity (n = 23) and 100% specificity (n = 4855) for phenobarbital in our existing LC−HRMS−ESI+ screening. The two negative results were the two whole‐blood samples with the lowest phenobarbital concentration (<1.8 mg/kg). Thus, a specialized screening is not necessary and use of this adduct likely enables screening for other barbiturates.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of phenobarbital and other barbiturates in forensic drug screening using positive electrospray ionization liquid chromatography−high resolution mass spectrometry

Høj

Mollerup

Rasmussen

et al. 2019

Drug Testing and Analysis

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“…These findings suggest that analysis of retrospective data is generally possible, e.g., if samples are initially collected in the same sampling tubes, sample storage and preparation is highly standardized, and routine methods are quality controlled as is typically the case in routine forensic analysis (Nielsen et al, 2016). Mollerup et al successfully applied a similar strategy to search for new markers/metabolites of valproic acid ingestion amenable to positive electrospray ionization (ESI) (Mollerup et al, 2019).…”

Section: Metabolomicsmentioning

confidence: 99%

“…Mollerup et al performed an interesting omics-based retrospective analysis to identify potential markers of valproic acid in blood that should allow the detection of valproic acid intake using the commonly applied positive ESI-MS mode. The antiepileptic drug valproic acid represents an important compound in forensic toxicological analysis, but can only be detected with negative ionization techniques or by GC-MS (Mollerup et al, 2019). A retrospective data evaluation of routinely measured samples on a qTOF instrument in ESI positive mode were performed forming a valproic acid positive group (determined by an additional targeted valproic acid method) and a negative reference group.…”

Section: Applications Of Metabolomics For Forensic (Toxicology) Purposesmentioning

confidence: 99%

Metabolomic Strategies in Biomarker Research–New Approach for Indirect Identification of Drug Consumption and Sample Manipulation in Clinical and Forensic Toxicology?

2019

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Drug of abuse (DOA) consumption is a growing problem worldwide, particularly with increasing numbers of new psychoactive substances (NPS) entering the drug market. Generally, little information on their adverse effects and toxicity are available. The direct detection and identification of NPS is an analytical challenge due to their ephemerality on the drug scene. An approach that does not directly focus on the structural detection of an analyte or its metabolites, would be beneficial for this complex analytical scenario and the development of alternative screening methods could help to provide fast response on suspected NPS consumption. A metabolomics approach might represent such an alternative strategy for the identification of biomarkers for different questions in DOA testing. Metabolomics is the monitoring of changes in small (endogenous) molecules (<1,000 Da) in response to a certain stimulus, e.g., DOA consumption. For this review, a literature search targeting “metabolomics” and different DOAs or NPS was conducted. Thereby, different applications of metabolomic strategies in biomarker research for DOA identification were identified: (a) as an additional tool for metabolism studies bearing the major advantage that particularly a priori unknown or unexpected metabolites can be identified; and (b) for identification of endogenous biomarker or metabolite patterns, e.g., for synthetic cannabinoids or also to indirectly detect urine manipulation attempts by chemical adulteration or replacement with artificial urine samples. The majority of the currently available literature in that field, however, deals with metabolomic studies for DOAs to better assess their acute or chronic effects or to find biomarkers for drug addiction and tolerance. Certain changes in endogenous compounds are detected for all studied DOAs, but often similar compounds/pathways are influenced. When evaluating these studies with regard to possible biomarkers for drug consumption, the observed changes appear, albeit statistically significant, too small to reliably work as biomarker for drug consumption. Further, different drugs were shown to affect the same pathways. In conclusion, metabolomic approaches possess potential for detection of biomarkers indicating drug consumption. More studies, including more sensitive targeted analyses, multi-variant statistical models or deep-learning approaches are needed to fully explore the potential of omics science in DOA testing.

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Overview of systematic toxicological analysis strategies and their coverage of substances in forensic toxicology

Rygaard

Pan

Nielsen

et al. 2023

Analytical Science Advances

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Systematic toxicological analysis (STA) is the process of using an adequate analytical methodology to detect and identify as many potentially toxicologically relevant compounds as possible in biological samples. STA is an important part of everyday routine work within forensic toxicology, and several methods for STA have frequently been published and reviewed independently. However, the many drugs and other substances involved, as well as the constant emergence of new ones, may pose a major challenge in STA, which often demands a strategy involving multiple analytical methods in parallel. Such strategies have been published and evaluated less frequently despite their relevance in forensic toxicology. This mini‐review briefly summarizes commonly applied methods for STA in forensic toxicology, including gas chromatography–mass spectrometry (GC–MS) and liquid chromatography–MS (LC–MS) methods, and highlights some of their potential pitfalls. Second, it provides an overview of previously reported strategies to conduct STA, including a presentation of the STA strategy applied in the authors’ laboratory. This involves broad drug screening by LC–high‐resolution MS, supported by targeted screening and quantification using LC–tandem MS, headspace (HS)‐GC–MS, HS‐GC–flame ionization detector and other complementary methods. The STA strategy aims to cover as many potentially relevant drugs as possible and seeks to reduce potential pitfalls arising in forensic casework. The review underlines that not every substance can be identified in all circumstances even with a comprehensive STA strategy.

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Retrospective analysis for valproate screening targets with liquid chromatography–high resolution mass spectrometry with positive electrospray ionization: An omics‐based approach

Cited by 25 publications

References 36 publications

Identification of phenobarbital and other barbiturates in forensic drug screening using positive electrospray ionization liquid chromatography−high resolution mass spectrometry

Identification of phenobarbital and other barbiturates in forensic drug screening using positive electrospray ionization liquid chromatography−high resolution mass spectrometry

Metabolomic Strategies in Biomarker Research–New Approach for Indirect Identification of Drug Consumption and Sample Manipulation in Clinical and Forensic Toxicology?

Overview of systematic toxicological analysis strategies and their coverage of substances in forensic toxicology

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