bims-metlip Biomed News
on Methods and protocols in metabolomics and lipidomics
Issue of 2023–12–03
43 papers selected by
Sofia Costa, Matterworks



  1. Methods Mol Biol. 2024 ;2737 123-132
      We present a quantitative clinical LC-MS/MS assay for the simultaneous analysis of buprenorphine, norbuprenorphine, and their glucuronide metabolites in human urine. The assay is based on the direct and hydrolysis-free sample preparation protocol, i.e., dilute and shoot, whereby clarified urine specimens are diluted in internal standard reagent and injected into the LC-MS/MS instrument. The analytical platform employs reversed-phase liquid chromatography for upfront separation and electrospray ionization multiple reaction monitoring MS detection via the triple-quadrupole (TSQ Quantiva) instrument. The assay has a quantitative analytical range of 5 ng/mL-1000 ng/mL represented at seven levels for each of the four analytes. A unique stable isotopically labeled analogue is used as internal standard for each analyte. For high-throughput performance, the assay can be multiplexed between two LC channels.
    Keywords:  Buprenorphines; Electrospray ionization (ESI); Glucuronides; High-throughput LC-MS/MS; Multiple reaction monitoring (MRM); Therapeutic drug monitoring
    DOI:  https://doi.org/10.1007/978-1-0716-3541-4_12
  2. Methods Mol Biol. 2024 ;2737 215-227
      In recent years a multitude of LC-MS/MS assays have been widely reported in commercial and clinical literature demonstrating the simultaneous analyses of dozens of drugs of abuse in human samples. The utility of such assays is meant to supplant the indirect detection based on the classical spectral library approach. Direct and simultaneous analysis via LC-MS/MS technology is made possible by fast acquisition rates in multiple reaction monitoring, as well as sensitivity and high selectivity of the technology for each individual analyte in a complex mixture. Hence, unlike immunoassays, which are not well-suited for the analyses of mixtures, and which may also be prone to false positives from potential interferences, quantitative LC-MS/MS analyses are feasible for complex patient mixtures of drugs of abuse. We hereby present a robust clinical LC-MS/MS assay for the simultaneous and semi-quantitative analysis of up to 62 drugs of abuse in human urine, representing major classes that include opiates, benzodiazepines, amphetamines, etc. The assay utilizes dilute and shoot, whereby the sample is diluted ten times in internal standard reagent and thereafter submitted to the LC-MS instrument, i.e., reversed-phase liquid chromatography coupled to the electrospray ionization multiple reaction monitoring analysis, via the TSQ Endura triple-quadrupole instrument. The assay employs stable isotope-labeled internal standards with a linear response in the 30-300 ng/mL range, effectively semi-quantitative, since this analytical range is well within typical immunoassay cutoffs for most drugs.
    Keywords:  Dilute and shoot; ESI-MRM-MS; Panel of drugs of abuse; Semi-quantitative
    DOI:  https://doi.org/10.1007/978-1-0716-3541-4_20
  3. Methods Mol Biol. 2024 ;2737 91-101
      We hereby present a fast, high-throughput, and clinical LC-MS/MS assay for the simultaneous analysis of barbiturates in human urine. It is deployed as a quantitative assay for phenobarbital, butalbital, pentobarbital/amobarbital, and secobarbital, as well as for confirmations following positive immunoassay drug screens in patient urine. Briefly, urine specimens are processed via dilute and shoot, i.e., by mixing the sample with 20 times volume of internal standard reagent and injecting 50 μL of that mixture into the analytical instrument. Chromatographic separation is performed using a reversed-phase C18 column in a mobile-phase system doped with <1 mM ammonium fluoride. Mass spectrometric detection occurs via negative-mode electrospray ionization multiple reaction monitoring in the TSQ Quantiva triple-quadrupole instrument. All the analytes in the mixture are detected and quantified simultaneously with respect to internal calibration in the range 20-2500 ng/mL. However, the assay cannot distinguish pentobarbital from amobarbital, which are isobaric analytes. Nonetheless, the assay is sensitive, robust, and amenable to harmonization with other assays that employ barbiturate cutoffs in the range of 20-150 ng/mL.
    Keywords:  Barbiturates; High-throughput LC-MS/MS; Multiple reaction monitoring (MRM); Multiplex HPLC; Negative-mode electrospray ionization (ESI)
    DOI:  https://doi.org/10.1007/978-1-0716-3541-4_9
  4. J Vis Exp. 2023 Nov 10.
      A significant challenge in the analysis of omics data is extracting actionable biological knowledge. Metabolomics is no exception. The general problem of relating changes in levels of individual metabolites to specific biological processes is compounded by the large number of unknown metabolites present in untargeted liquid chromatography-mass spectrometry (LC-MS) studies. Further, secondary metabolism and lipid metabolism are poorly represented in existing pathway databases. To overcome these limitations, our group has developed several tools for data-driven network construction and analysis. These include CorrelationCalculator and Filigree. Both tools allow users to build partial correlation-based networks from experimental metabolomics data when the number of metabolites exceeds the number of samples. CorrelationCalculator supports the construction of a single network, while Filigree allows building a differential network utilizing data from two groups of samples, followed by network clustering and enrichment analysis. We will describe the utility and application of both tools for the analysis of real-life metabolomics data.
    DOI:  https://doi.org/10.3791/65512
  5. Methods Mol Biol. 2024 ;2737 377-386
      We hereby present a direct, clinical LC-MS/MS assay for the simultaneous analysis of opiates and opioids in human urine. The assay is used as confirmations as well as a quantitative assay following immunoassay urine drug screens. Hence, the utility is extended to report opiate/opioid levels in the range 10-1000 ng/mL for each of the 13 analytes, which include morphine and metabolites; codeine and metabolites; as well as synthetics such as heroin metabolites, dihydrocodeine, oxycodone, and naloxone. The assay employs dilute and shoot, utilizing reversed-phase liquid chromatography for mixture separation and positive-mode electrospray-ionization multiple-reaction-monitoring for MS detection in the TSQ Endura triple-quadrupole (QqQ) instrument. Thereafter, quantitative analysis is based on the linear calibration using six reference standards, whereby the instrument response for each analyte at a given concentration is normalized against stable isotope labeled internal standard.
    Keywords:  Codeine; Heroin metabolites; LC-MS/MS; Metabolites; Morphine; Multiple-reaction-monitoring (MRM); Opiates; Synthetic opioids
    DOI:  https://doi.org/10.1007/978-1-0716-3541-4_34
  6. Methods Mol Biol. 2024 ;2737 103-111
      We hereby present a fast, high-throughput, and clinical LC-MS/MS assay for the simultaneous analysis of benzodiazepines in human urine. The assay is used as both a confirmations and semi-quantitative assay for the abovementioned drugs of abuse following immunoassay urine drug screens. Urine levels are reported in the range of 25 ng/mL-500 ng/mL for each of the 22 analytes, based on a six-level calibration and using a subset (10) of stable isotopically labeled analogues as internal standards. The urine sample is clarified, diluted ten times in internal standard reagent, and thereafter injected into the LC-MS/MS instrument. Reversed-phase liquid chromatography is used to separate the mixture, and the TSQ Endura triple-quadrupole (QqQ) MS instrument performs detection via positive-mode electrospray ionization multiple reaction monitoring.
    Keywords:  Benzodiazepines; Electrospray ionization (ESI); High-throughput LC-MS/MS; Multiple reaction monitoring (MRM)
    DOI:  https://doi.org/10.1007/978-1-0716-3541-4_10
  7. Methods Mol Biol. 2024 ;2737 15-23
      We hereby present a fast and high-throughput LC-MS/MS assay for the simultaneous analysis of amphetamines and cocaine in human urine. The assay is used for confirmations following immunoassay urine drug screens as well as a quantitative assay to report actual urine concentrations in the range 30-10,000 ng/mL for each of the seven analytes, namely, amphetamine; methamphetamine; phentermine; methylenedioxyamphetamine; 3,4-methylenedioxymethamphetamine; methylenedioxy-ethyl-amphetamine; and a cocaine metabolite, benzoylecgonine. The assay derives its efficacy from minimal sample preparation via dilute and shoot. The platform is based on reversed-phase liquid chromatography coupled to the TSQ Endura triple-quadrupole (QqQ) MS instrument for detection via electrospray ionization multiple-reaction monitoring MS. The quantitative analysis is based on the linear calibration whereby the instrument response for each analyte at a given concentration is normalized against stable isotope-labeled internal standard. In addition, the assay can be multiplexed across more than one LC channel to obtain high-sample throughput.
    Keywords:  Amphetamines; Cocaine; Drugs of abuse; Electrospray ionization (ESI); High-throughput LC-MS/MS; Multiple-reaction monitoring (MRM); Multiplex HPLC
    DOI:  https://doi.org/10.1007/978-1-0716-3541-4_2
  8. Ther Drug Monit. 2023 Nov 22.
       BACKGROUND: Fosfomycin is an antibiotic recently repurposed as a potential combination treatment for difficult-to-treat Gram-negative bacterial infections. The pharmacokinetic features of fosfomycin have demonstrated that different pathophysiologic alterations may affect its exposure. Therapeutic drug monitoring may improve real-time management of fosfomycin therapy in different clinical scenarios.
    OBJECTIVES: To develop and validate a fast and sensitive liquid chromatography - tandem mass spectrometry method for measuring fosfomycin in human plasma microsamples (3 µL).
    METHODS: Analysis was preceded by a user-friendly pre-analytical single-step process performed via a rapid chromatographic run of 2.5 minutes, followed by negative electrospray ionization and detection on a high-sensitivity triple quadrupole tandem mass spectrometer operated in the multiple reaction monitoring mode. European Medicines Agency guidelines were used to validate the specificity, sensitivity, linearity, precision, accuracy, matrix effects, extraction recovery, limits of quantification, and stability of the analytical method.
    RESULTS: The new assay produced accurate (BIAS%: 0.9-9.1) and precise (coefficient of variation [CV]%: 8.1-9.5) measurements of fosfomycin over a concentration range of 1-1000 mg/L. Overall, analyte recovery was consistent (mean values: 91.2%-97.2%) at all tested concentration levels. The analyte was also stable in human plasma and the final extract under various storage conditions. The clinical applicability of the assay was confirmed through quantitation of plasma samples obtained from patients.
    CONCLUSIONS: A sensitive liquid chromatography - tandem mass spectrometry method for measuring fosfomycin in plasma was developed and validated according to the European Medicines Agency criteria. Quantitation of fosfomycin in clinical plasma samples confirmed that the assay is suitable for therapeutic drug monitoring in clinical scenarios.
    DOI:  https://doi.org/10.1097/FTD.0000000000001158
  9. Adv Exp Med Biol. 2024 ;1440 57-71
      Oxysterols are involved in a plethora of biological processes, including a wide variety of diseases. Therefore, monitoring oxysterols is important for obtaining a deeper understanding of their biological roles and utilizing them as, for example, biomarkers. However, oxysterols can be challenging compounds to study, as they can be very similar in chemical structure but still have distinct biological roles. In addition, oxysterols may be difficult to detect, even with advanced analytical instrumentation. We here focus on the use of liquid chromatography-mass spectrometry (LC-MS) for the analysis of oxysterols, with an additional focus on the steps needed to prepare oxysterols for LC-MS. Steps can include chemical modification of the oxysterols for improving LC-MS sensitivity and adding chemicals that can reveal if the oxysterol levels have been perturbed during preparation. We then round off with descriptions and applications of various sample preparations for different biological matrices, from blood to cells, and biosamples with emerging attention, for example, exosomes and organoids. Taken together, oxysterol analysis is highly compatible with a wide variety of biosamples, allowing for a deeper understanding of these challenging analytes.
    Keywords:  Biosamples; Derivatization; Exosome; Liquid chromatography–mass spectrometry; Organoids; Oxysterols; Sample preparation
    DOI:  https://doi.org/10.1007/978-3-031-43883-7_4
  10. Heliyon. 2023 Nov;9(11): e21921
       Background: Given the growing interest in studying the role of choline and phosphocholine in the development and progression of tumor pathology, in this study we describe the development and validation of a fast and robust method for the simultaneous analysis of choline and phosphocholine in human plasma.
    Methods: Choline and phosphocholine quantification in human plasma was obtained using a hydrophilic interaction liquid chromatography-tandem mass spectrometry technique. Assay performance parameters were evaluated using EMA guidelines.
    Results: Calibration curve ranged from 0.60 to 38.40 μmol/L (R2 = 0.999) and 0.08-5.43 μmol/L (R2 = 0.998) for choline and phosphocholine, respectively. The Limit Of Detection of the method was 0.06 μmol/L for choline and 0.04 μmol/L for phosphocholine. The coefficient of variation range for intra-assay precision is 2.2-4.1 % (choline) and 3.2-15 % (phosphocholine), and the inter-assay precision range is < 1-6.5 % (choline) and 6.2-20 % (phosphocholine). The accuracy of the method was below the ±20 % benchmarks at all the metabolites concentration levels. In-house plasma pool of apparently healthy adults was tested, and a mean concentration of 15.97 μmol/L for Choline and 0.34 μmol/L for Phosphocholine was quantified.
    Conclusions: The developed method shows good reliability in quantifying Choline and Phosphocholine in human plasma for clinical purposes.
    Keywords:  Choline; HILIC HPLC-MS; Human plasma; Phosphocholine; method validation
    DOI:  https://doi.org/10.1016/j.heliyon.2023.e21921
  11. Methods Mol Biol. 2024 ;2737 397-404
      Pentobarbital is a short-acting barbiturate with anticonvulsant and sedative-hypnotic properties. Pentobarbital may be used to induce sedation, control seizures, induce coma, and to manage patients with traumatic brain injury. In traumatic brain injury, use of pentobarbital is known to reduce both cerebral blood flow and oxygen consumption, which reduces intracranial pressure and cerebral ischemia. As there are currently no known commercially available methods for quantification, a quick and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method is described here for the quantification of pentobarbital. The analyte and internal standard, D5-pentobarbital, were extracted from human serum via solid phase extraction prior to LC-MS/MS analysis utilizing electrospray ionization (ESI) in negative ionization mode. Confirmation and quantitation of pentobarbital was performed using multiple reaction monitoring (MRM). The method was linear from 0.5 to 100 μg/mL with imprecision less than 5% coefficient of variability. Pentobarbital eluted at 2.61 min and the total run time was 7 min. The method only requires 100 μL of serum due to the high physiologic concentrations required for sedation/coma.
    Keywords:  Pentobarbital; Sedative-hypnotic; Tandem mass spectrometry; Traumatic brain injury
    DOI:  https://doi.org/10.1007/978-1-0716-3541-4_36
  12. Methods Mol Biol. 2024 ;2737 113-121
      Bupropion is a medication commonly used to treat depression and help people quit smoking. However, it has the potential to be misused or diverted, so it is important to have accurate and sensitive methods to detect it in bodily fluids. We present a fast and dependable quantitative LC-MS/MS method for measuring bupropion levels in urine. This method involves enzymatic hydrolysis and separation using a reversed-phase C18 column, where the effectiveness of the hydrolysis is monitored using morphine-3-b-D-glucuronide. The analysis is conducted using an AB Sciex 3500 mass spectrometer with dual-channel LC system.
    Keywords:  Bupropion; Liquid chromatography; Mass spectrometry; Therapeutic drug monitoring
    DOI:  https://doi.org/10.1007/978-1-0716-3541-4_11
  13. Methods Mol Biol. 2024 ;2737 347-357
      Olanzapine (Zyprexa™) is indicated for the treatment of schizophrenia and bipolar disorder. Olanzapine is metabolized to inactive metabolites; therefore, this assay measures the concentrations of olanzapine and internal standard, olanzapine-D3. This procedure provides instructions for quantitating levels of olanzapine in blood serum specimens. An internal standard (IS) solution consisting of the deuterated analogue of olanzapine is added to an aliquot of the patient serum or plasma, standards, and positive controls. The drugs of interest are separated from the biological fluid using solid phase extraction. The dried extracts are reconstituted in mobile phase and separated by liquid chromatography. The solution is introduced into an Agilent 6470A triple quadrupole tandem mass spectrometer via positive mode electrospray ionization (ESI) utilizing multiple reaction monitoring (MRM). Quantitation is performed by comparison to a calibration curve, using Indigo® (Ascent) software.
    Keywords:  Mass spectrometry; Olanzapine; Plasma; Serum
    DOI:  https://doi.org/10.1007/978-1-0716-3541-4_32
  14. Methods Mol Biol. 2024 ;2737 337-345
      Nicotine is a naturally occurring and highly addictive chemical used in e-cigarettes, cigarettes, chewing tobacco, and other tobacco products as well as in nicotine replacement therapies. The negative health consequences of using nicotine-containing products are well known. In fact, smoking remains the leading cause of preventable disease, disability, and death in the United States. Measurement of nicotine and its metabolites, cotinine and 3-OH-cotinine, offers an objective method to evaluate nicotine exposure and the associated health risks. In this chapter, we describe a quick and reliable isotope dilution LC-MS/MS method for the quantitation of these three compounds in 60 μL of human urine following a simple sample preparation procedure. Electrospray Ionization (ESI) in positive mode is used to introduce the analytes into the mass spectrometer and quantitation is achieved using Multiple Reaction Monitoring (MRM). The analytical measurable ranges for nicotine and cotinine are 10-2500 ng/mL and 20-5000 ng/mL for 3-OH-cotinine.
    Keywords:  3-OH-cotinine; Chromatography; Cotinine; LC-MS/MS; Mass spectrometry; Nicotine
    DOI:  https://doi.org/10.1007/978-1-0716-3541-4_31
  15. Methods Mol Biol. 2024 ;2737 79-90
      In the method described here, an aliquot of a urine sample is analyzed to detect barbiturates through dilution and ultra-high-performance chromatography-tandem mass spectrometry (UPLC-MS/MS) using deuterated internal standards. This assay detects the presence of nine barbiturate drugs-amobarbital, barbital, butalbital, butabarbital, mephobarbital, secobarbital, pentobarbital, phenobarbital, and thiopental. This protocol describes two LC separation methods-first LC method (2.2 min/sample) is intended to be used as a first step of the analysis that does not separate amobarbital and pentobarbital, and a second, longer (2.7 min/sample) LC method is intended to be used only for samples which have a peak in the amobarbital/pentobarbital retention time on the shorter LC method. Since the frequency at which amobarbital and pentobarbital are observed in clinical populations is low, the shorter LC method helps gain efficiency in a high-volume laboratory environment. Additional features of this protocol that help in efficiency gain are automated extraction using Hamilton™ liquid handling system and algorithmic data review using Ascent™ software.
    Keywords:  Barbiturates; Distinguishing amobarbital and pentobarbital; Liquid chromatography; Mass spectrometry
    DOI:  https://doi.org/10.1007/978-1-0716-3541-4_8
  16. RSC Adv. 2023 Nov 16. 13(48): 34157-34166
      Vitamin D plays an important role in calcium homeostasis. Recent studies indicate that vitamin D deficiency has become a major public health problem. In order to define vitamin D status, many analytical methods were used to quantify 25-hydroxyvitamin D (25OHD), as circulating 25OHD is regarded as the best indicator to evaluate vitamin D status. The current LC-MS/MS technology is internationally recognized as the "gold standard" for the detection of vitamin D and its metabolites. The impediment to the analysis of vitamin D metabolites is the low level of 25OHD and 1,25(OH)2D. Therefore, it is challenging to achieve the desired sensitivity and accuracy in the determination of trace vitamin D compounds in biological liquids. Here, a method based on liquid-liquid extraction in combination with derivatization, followed by liquid chromatography-electrospray/tandem mass spectrometry was developed for determination of the vitamin D metabolites, including 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, 1α,25-dihydroxyvitamin D2 and 1α,25-dihydroxyvitamin D3. The method was simple and rapid, and it was validated with good linearity (R2 > 0.998), excellent recovery (average value with 81.66-110.31%) and high precision of intra-day and inter-day (0.06-6.38% and 0.20-6.82%). The values of limit of detection (LOD) and limit of quantitation (LOQ) were as low as 0.3 ng mL-1 and 1.0 ng mL-1, respectively. Finally, the developed method was successfully applied to determination of the vitamin D metabolites from the human serum samples of healthy subjects and patients with diabetes as well as hyperlipidemia.
    DOI:  https://doi.org/10.1039/d3ra05700c
  17. Methods Mol Biol. 2024 ;2737 55-65
      Antifungal therapy with triazole drugs including posaconazole, voriconazole, itraconazole, and its active metabolite hydroxyitraconazole is routinely accompanied by therapeutic drug monitoring to ensure optimal dosing. The method presented here simultaneously quantitates these compounds in serum by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Specimen preparation includes protein precipitation with a methanol and acetonitrile mixture, centrifugation, and filtration. Analyte separation is achieved by reverse-phase chromatography using a dC18 column and a linear gradient of methanol in water. Analytes are detected by multiple reaction monitoring mass spectrometry and quantitated by comparison to a standard curve.
    Keywords:  Antifungal; Fungal infection; Hydroxyitraconazole; Itraconazole; Mass spectrometry; Posaconazole; Therapeutic drug monitoring; Triazole; Voriconazole
    DOI:  https://doi.org/10.1007/978-1-0716-3541-4_6
  18. Anal Methods. 2023 Nov 27.
      Aminobutyric acid has structural isomers (α-, β-, and γ-aminobutyric acids) and enantiomers (D/L-forms) with various unique functions. Therefore, a quantitative method for determining the content of each aminobutyric acid must be developed. In general, quantitative simultaneous analysis of multiple compounds is conducted via high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS). However, simultaneous separation and highly sensitive detection of all aminobutyric acids are complicated, so highly sensitive analytical methods for the separation and identification of each compound have not yet been established. We previously developed highly sensitive chiral resolution labeling reagents. Herein, we propose a highly sensitive analytical method for the simultaneous separation and identification of all aminobutyric acids via LC-MS and labeling with our original highly sensitive chiral resolution labeling reagent, 1-fluoro-2,4-dinitrophenyl-5-L-valine-N,N-dimethylethylenediamine amide (L-FDVDA). The labeling reagent was completely bound to all aminobutyric acids through incubation overnight (>15 h) at 50 °C. Additionally, the labeled aminobutyric acids could be stored for at least 1 week at 4 °C. Furthermore, we demonstrated simultaneous separation and identification of aminobutyric acids in biological samples and foods through LC-MS using a C18 column after labeling with L-FDVDA. Our method is expected to be adopted for the analysis of the contents of all aminobutyric acids in biological and clinical samples as well as various foods.
    DOI:  https://doi.org/10.1039/d3ay01665j
  19. Methods Mol Biol. 2024 ;2737 229-247
      Regular monitoring of pain management and substance use disorder patients through urine drug screening is important for assessing patient compliance with prescribed drugs and abstinence from non-prescribed drugs. Sample analysis is commonly performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) as multiple drugs and metabolites can be monitored from one sample. However, challenges faced in developing an LC-MS/MS method for multiple analytes in urine include variability in matrix and concentration from sample to sample and variable chemistry of many pain management drugs and associated metabolites affecting accuracy and precision of results. We describe here an LC-MS/MS method for analysis of 41 drugs and metabolites commonly prescribed for pain management patients. The developed method uses enzymatic hydrolysis followed by cation exchange solid phase extraction. Resorufin-glucuronide is used as an internal hydrolysis control to monitor hydrolysis in each patient sample and minimize false negatives. Analysis was performed using an Agilent 6470 mass spectrometer in dynamic multiple reaction monitoring mode.
    Keywords:  Amphetamines; Benzodiazepines; Gabapentin; Hydrolysis; Liquid chromatography; Mass spectrometry; Opioids; Pain panel; Urine drug testing
    DOI:  https://doi.org/10.1007/978-1-0716-3541-4_21
  20. Methods Mol Biol. 2024 ;2737 25-32
      Antiepileptic drugs (AEDs) have been used to control epilepsy. More than 17 new AEDs, including gabapentin (GPN), lacosamide (LCM), perampanel (PER), pregabalin (PRG), rufinamide (RFM), and vigabatrin (VGB) have been approved and marketed since 1989. Accurate measurement of serum concentration of the antiepileptic drugs is crucial to achieve optimal efficacy and avoid adverse events. We describe an accurate and precise liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of GPN, LCM, PER, PRG, RFM, and VGB in serum. The method requires a small volume of sample (10 μL) and has a total chromatographic run time of 4 min for simultaneous measurement of these drugs. The method showed good accuracy with a bias of -0.2-5%. The intra- and inter-day imprecision were less than 5.0% for all the analytes. The linear assay ranges were 0.3-26 μg/mL for GPN, 0.15-24 μg/mL for LCM, 7.4-1881 ng/mL for PER, 0.03-13 μg/mL for PRG, 0.78-90 μg/mL for RFM, and 0.3-43 μg/mL for VGB.
    Keywords:  Antiepileptic drugs; Epilepsy; Gabapentin; Lacosamide; Liquid chromatography-tandem mass spectrometry; Perampanel; Pregabalin; Rufinamide; Vigabatrin
    DOI:  https://doi.org/10.1007/978-1-0716-3541-4_3
  21. Adv Exp Med Biol. 2024 ;1440 73-87
      Mass spectrometry imaging (MSI) is a new technique in the toolbox of the analytical biochemist. It allows the generation of a compound-specific image from a tissue slice where a measure of compound abundance is given pixel by pixel, usually displayed on a color scale. As mass spectra are recorded at each pixel, the data can be interrogated to generate images of multiple different compounds all in the same experiment. Mass spectrometry (MS) requires the ionization of analytes, but cholesterol and other neutral sterols tend to be poorly ionized by the techniques employed in most MSI experiments, so despite their high abundance in mammalian tissues, cholesterol is poorly represented in the MSI literature. In this chapter, we discuss some of the MSI studies where cholesterol has been imaged and introduce newer methods for its analysis by MSI. Disturbed cholesterol metabolism is linked to many disorders, and the potential of MSI to study cholesterol, its precursors, and its metabolites in animal models and from human biopsies will be discussed.
    Keywords:  24S-hydroxycholesterol; Cholesterol; Mass spectrometry; Mass spectrometry imaging; Neurodegeneration; Oxysterol
    DOI:  https://doi.org/10.1007/978-3-031-43883-7_5
  22. Bio Protoc. 2023 Nov 20. 13(22): e4880
      Dolichyl phosphates (DolP) are ubiquitous lipids that are present in almost all eukaryotic membranes. They play a key role in several protein glycosylation pathways and the formation of glycosylphosphatidylinositol anchors. These lipids constitute only ~0.1% of total phospholipids, and their analysis by reverse phase (RP) liquid chromatography-high-resolution mass spectrometry (LC-HRMS) is challenging due to their high lipophilicity (log P > 20), poor ionization efficiency, and relatively low abundance. To overcome these challenges, we have introduced a new approach for DolP analysis by combining trimethylsilyldiazomethane (TMSD)-based phosphate methylation and HRMS analysis. The analytical method was validated for its reproducibility, sensitivity, and accuracy. The established workflow was successfully applied for the simultaneous characterization and quantification of DolP species with different isoprene units in lipid extracts of HeLa and Saccharomyces cerevisiae cells.
    Keywords:  DolP; Dolichyl phosphate; LC-MS; LC–HRMS; Lipid analysis; Methylation; TMSD
    DOI:  https://doi.org/10.21769/BioProtoc.4880
  23. Methods Mol Biol. 2024 ;2737 43-54
      Antiepileptic drugs (AEDs) are a chemically diverse group of medications that are used to control seizures and different clinical forms of epilepsy. AEDs can be used as single agents but are commonly administered in combination, as a multi-drug regimen. AEDs have narrow therapeutic windows. Therapeutic ranges may not be properly defined, and symptoms of toxic serum concentrations may include increased frequency of seizures, as seen when AED concentrations are subtherapeutic. Pentobarbital, a barbiturate, is a potent anti-seizure medication, but it is also used in the treatment of head injury. Therapeutic drug monitoring (TDM) is required for optimal treatment of epilepsy. The method presented here is designed to measure serum concentrations of six commonly administered antiepileptic drugs (levetiracetam (Keppra), lamotrigine, lacosamide, 10-hydroxycarbazepine (oxcarbazepine metabolite), topiramate, zonisamide) and that of pentobarbital by LC-MS/MS. Liquid-liquid sample extraction is followed by reversed-phase chromatography using biphenyl HPLC column and gradient elution. Two MRM transitions are monitored for each drug, and their heavy isotope labeled internal standards. Six-point calibration curve is generated with each batch of analysis for quantitation of AEDs. The method's AMR covers the clinically relevant concentration range for each AED. The method has <10% CV throughout the AMR, is free of matrix effect commonly found in clinical samples, and is free from cross reactivity by other AEDs.
    Keywords:  10-Hydroxycarbazepine; Antiepileptic drugs; Keppra; Lacosamide; Lamotrigine; Levetiracetam; Liquid chromatography tandem mass spectrometry; Oxcarbazepine metabolite; Pentobarbital; Therapeutic drug monitoring; Topiramate; Zonisamide
    DOI:  https://doi.org/10.1007/978-1-0716-3541-4_5
  24. Methods Mol Biol. 2024 ;2737 195-214
      In recent years, the use of oral fluid as a testing matrix for drug analysis has become increasingly popular due to its benefits, such as a possibility for direct observation of a sample collection and, thus, a lower risk of adulteration. To address this trend, we have developed a quantitative LC-MS/MS method that can simultaneously analyze 49 commonly prescribed compounds in oral fluid. The assay is performed on an AB Sciex 4500 electrospray ionization mass spectrometer in multiple reaction monitoring mode.
    Keywords:  Illicit drugs; LC-MS/MS; Liquid chromatography; Mass spectrometry; Oral fluid; Saliva; Therapeutic drug monitoring
    DOI:  https://doi.org/10.1007/978-1-0716-3541-4_19
  25. Methods Mol Biol. 2024 ;2737 161-174
      Δ8-Tetrahydrocannabinol (Δ8-THC) and cannabidiol (CBD) are increasingly popular cannabinoids. Measuring metabolites in urine is an important tool for detecting use and/or exposure as well as for monitoring elimination of these two drugs. Distinguishing between the metabolite 11-nor-9-carboxy-Δ8-tetrahydrocannabinol (Δ8-THC-COOH) and the analogous metabolite of the more common and naturally abundant Δ9-THC: 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (Δ9-THC-COOH) is analytically challenging due to structural similarities between the two compounds. Here, we present a method for separating the positional isomers Δ8-THC-COOH and Δ9-THC-COOH as well as 7-carboxy cannabidiol (CBD-COOH) in urine that includes reverse-phase solid-phase extraction (SPE), followed by liquid chromatographic separation with a perfluorophenyl column, and detection by tandem mass spectrometry (LC-MS/MS).
    Keywords:  CBD; Cannabis; Delta-8; Delta-9; Marijuana; THC
    DOI:  https://doi.org/10.1007/978-1-0716-3541-4_16
  26. J Chromatogr A. 2023 Nov 26. pii: S0021-9673(23)00760-4. [Epub ahead of print]1713 464535
      With the development of therapeutic oligonucleotides for antisense and gene therapies, the demand for analytical methods also increases. For the analysis of complex samples, for example plasma samples, where the use of mass detection is essential, hydrophilic interaction liquid chromatography is a suitable choice. The aim of the present work was to develop a method for separation and identification of the oligonucleotide impurities and metabolites by hydrophilic interaction liquid chromatography. First of all, the effects of different chromatographic conditions (e.g. pH of the aqueous part of the mobile phase, buffer concentration, column temperature) on the retention and separation of phosphorothioate oligonucleotides standards on the amide stationary phase were investigated. A set of model oligonucleotides containing a fully modified 21mer and its typical impurities (shortmers and oligonucleotides with different number of thiophosphate modifications) was used. The results showed that the concentration of the salt in the mobile phase as well as its pH, are the most influential parameters with regard to peak shape and separation. The knowledge gained was applied to the analysis of an unpurified 18mer oligonucleotides, analogues of the drug nusinersen used for the treatment of spinal muscular atrophy. The successful separation and identification of twenty-six and twenty-eight impurities was performed with the developed HILIC method. The method was applied to analysis of nusinersen metabolites of serum samples of patients treated with Spinraza.
    Keywords:  Amide stationary phase; Hydrophilic interaction liquid chromatography; Impurities and metabolites; Nusinersen; Phosphorothioate oligonucleotides
    DOI:  https://doi.org/10.1016/j.chroma.2023.464535
  27. Conserv Physiol. 2023 ;11(1): coad081
      We describe a non-invasive method for profiling selected hormones, pharmaceuticals and personal care products (PPCPs) in killer whales (Orcinus orca) based on analysis of faecal samples by liquid chromatography tandem mass spectrometry (LC-MS/MS). The method targets 21 compounds of interest including glucocorticoids, mineralocorticoids, androgens, estrogens, progestogens, selective serotonin uptake inhibitors and an antibacterial/antifungal agent. This method is suitable for routine simultaneous determination of target compounds in killer whale faecal samples as well as validation of immunoassays for the detection and measurement of steroid hormones in faeces. The optimized method involves extraction of freeze-dried faecal material with reagent alcohol and water followed by isolation of the analytes using solid phase extraction with hydrophilic-lipophilic balance cartridges and liquid-liquid extraction with methyl tertiary-butyl ether. Reconstituted extracts were analysed by LC-MS/MS using an electrospray ionization interface. Method limit of quantification ranged from 0.06 to 45.2 ng/g in freeze-dried faecal samples. Except for sertraline, triclosan and estradiol (which was not recovered at the lowest spiked concentration), average intra- and inter-day precisions were within 10%, and average recoveries were between 89.3% and 129.3%, for faecal samples spiked with 5.3, 26.7 or 133 ng/g of each analyte. The method was applied successfully to the analysis of hormones and PPCPs in whale faeces during which 17α-hydroxyprogesterone, a common intermediate in steroid biosynthesis that cross-reacts with precursors and sulphated conjugates in immunoassays, was identified and quantified in all samples.
    Keywords:  Killer whale faeces; liquid chromatography–tandem mass spectrometry; pharmaceuticals and personal care products; steroid hormones
    DOI:  https://doi.org/10.1093/conphys/coad081
  28. Methods Mol Biol. 2024 ;2737 387-395
      Oxcarbazepine (Trileptal®) has been found effective in the treatment of tonic-clonic seizures and partial seizures with or without secondary generalization, with fewer side effects than traditional therapy. Oxcarbazepine is a keto analogue of carbamazepine. It is rapidly reduced to 10-monohydroxy carbamazepine (MHD), its active metabolite. This assay measures concentrations for oxcarbazepine metabolite (MHD), internal standard (MHD 13C6) solution is added to all the patient specimens resulting in precipitation of proteins. The analytes are separated using a Phenomenex Kinetex C18 column and are detected with a mass spectrophotometer utilizing multiple reaction monitoring (MRM). The analytes are qualitatively identified and quantitated from a calibration curve generated from calibrators included in the run.
    Keywords:  Licarbazepine; Mass spectrometry; Monohydroxy-carbamazepine (MHD); Oxcarbazepine; Plasma; Serum
    DOI:  https://doi.org/10.1007/978-1-0716-3541-4_35
  29. Pak J Pharm Sci. 2023 Sep;36(5(Special)): 1597-1607
      A rapid, highly specific and sensitive UPLC-MS/MS method was developed for the determination of Quetiapine Fumarate, a therapeutic drug for various psychiatric disorders, in human plasma. The samples were pretreated using a protein precipitation method, followed by chromatographic separation using a column (Kinetex C18, 2.6µm 50*2.1mm) equipped with an ESI source and MRM mode mass spectrometer. In the validation results of the method, the analyte quetiapine showed a peak at approximately 1.0 minute and exhibited good linearity within the concentration from 2.5 to 2000ng/mL. The intra- and inter-batch precision CV% were within the range of -1.3% to 7.7% and precision of intra- and inter-batch were below 15.0%. Furthermore, this method demonstrated low matrix effects and high recovery rates. The quetiapine plasma sample solution remained stable at room temperature for 25 hours and following 4 freeze-thaw cycles. The prepared samples remained stable in the autosampler (The temperature control of the autosampler was 5oC) for 185 hours and after four freeze-thaw cycles at -20oC and -70oC for 40 days. The present work effectively employed this approach to investigate the pharmacokinetics of orally administered quetiapine fumarate tablets in a cohort of healthy Chinese individuals, both in a fasting state and after a meal.
  30. Methods Mol Biol. 2024 ;2737 265-273
      Ethyl glucuronide and ethyl sulfate emerged as the biomarkers of choice for detection of ethanol use as the required sample is urine, enabling easy and noninvasive collection. Further, these biomarkers have a longer detection window in urine than blood ethanol. A liquid chromatography-tandem mass spectrometry method was developed and clinically validated using electrospray ionization in negative mode and selected reaction monitoring. A simple dilution was used for sample preparation on 100 microliters of urine. Gradient elution had a run time of 7 min. The reportable range was established to be 180-100,000 ng/mL for ethyl glucuronide and 50-46,600 ng/mL for ethyl sulfate and between-run imprecision was <7% for both analytes.
    Keywords:  Alcohol; Ethanol; Ethyl glucuronide; Ethyl sulfate; LC-MS/MS; Mass spectrometry
    DOI:  https://doi.org/10.1007/978-1-0716-3541-4_24
  31. Methods Mol Biol. 2024 ;2737 443-452
      The thiopurine drugs, azathioprine, mercaptopurine, and thioguanine, are widely used in the treatment of several malignant and nonmalignant diseases. These inactive prodrugs undergo extensive metabolism to form active cytotoxic metabolites, which act mainly by incorporating into DNA and affecting cell replication. Thiopurine methyltransferase is a highly variable cytosolic enzyme that catalyzes the S-methylation of the thiopurine bases-an inactivating pathway. Patients with low-activity variants of TPMT can be affected by pronounced pharmacologic effects when receiving thiopurine medications. Clinical studies have reported significant interpatient variability in intracellular thiopurine metabolite concentrations in patients receiving thiopurine therapy. In this chapter, we present an LC-MS/MS method to monitor the thiopurine metabolites: 6-thioguanine nucleotides and 6-methylmercaptopurine derivatives in human erythrocytes. This method utilizes acid hydrolysis to release the bases and improves upon previously published procedures by utilizing stable isotope internal standards and a more efficient chromatographic separation.
    Keywords:  LC-MS/MS; Mercaptopurine; Therapeutic drug monitoring; Thioguanine
    DOI:  https://doi.org/10.1007/978-1-0716-3541-4_41
  32. Methods Mol Biol. 2024 ;2737 329-336
      Mycophenolate mofetil (MMF) and sodium mycophenolate are commonly prescribed immunosuppressive drugs for patients who have undergone solid organ transplant. Therapeutic drug monitoring (TDM) of these drugs is performed by assessing mycophenolic acid (MPA) in plasma. Due to the large inter-individual variability and narrow therapeutic range, the precise determination of systemic MPA concentration carries great clinical significance. We present a rapid, sensitive, specific, and robust liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantitation of MPA in plasma. A Waters Xevo TQ-S Micro mass spectrometer coupled to a Water's Acquity liquid chromatography system was used in positive electrospray ionization (ESI) mode. MPA quantitation was achieved using multiple reaction monitoring (MRM). Mycophenolic acid carboxybutoxy ether (MPAC) was employed as an internal standard. The method is linear from 0.25 to 40.00 mg/L, has intra-assay (N = 24) imprecision of 2.7% at 1.57 mg/L and 3.9% at 4.61 mg/L and inter-assay (N = 20 days) imprecision of 4.0% at 1.62 mg/L and 5.6% at 4.68 mg/L.
    Keywords:  Liquid chromatography; Mass spectrometry; Mycophenolic acid; Plasma; Quantification
    DOI:  https://doi.org/10.1007/978-1-0716-3541-4_30
  33. Methods Mol Biol. 2024 ;2737 319-327
      Accurate measurement of the glomerular filtration rate (GFR) is essential for detecting renal insufficiency in living kidney donors. Iohexol is a "near-ideal" exogenous filtration marker for GFR measurement that has attracted increasing interest in clinical practice because it is non-toxic, non-radioactive, readily available, and easy to measure. In this chapter, we describe a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to measure iohexol in serum and to calculate GFR based on the rate of iohexol clearance. In this procedure, the contrast agent iohexol is administrated to the study subject in an outpatient setting, and three timed blood samples are collected. The serum proteins are precipitated, and the supernatant containing iohexol and the internal standard 2H5-iohexol is diluted prior to LC-MS/MS analysis. The LC-MS/MS method utilizes a Thermo Vanquish UHPLC coupled with TSQ Endura triple quadruple mass spectrometer, with a total run time of 2.5 min. The LC-MS/MS method has demonstrated good analytical performances, and the workflow can be used to reliably measure GFR in apparently healthy individuals without impaired renal function, such as living kidney donors.
    Keywords:  Brochner-Mortensen correction; Iohexol serum clearance; Isotopically labeled internal standard; LC-MS/MS; Measured GFR
    DOI:  https://doi.org/10.1007/978-1-0716-3541-4_29
  34. Methods Mol Biol. 2024 ;2737 453-463
      Treosulfan is a structural analog of the alkylating agent busulfan which has been shown in clinical trials to exhibit comparable myeloablative activity while causing fewer serious side effects. Treosulfan is currently being considered for FDA approval in combination with fludarabine, one of the most commonly used myeloablative agents, as a conditioning regimen prior to hematopoietic stem cell transplantation (HSCT). Because plasma concentrations of both treosulfan and fludarabine exhibit significant interindividual variability, therapeutic drug monitoring (TDM) is indicated to ensure dosages are administered that maximize efficacy while minimizing toxicity. In this chapter, we describe a rapid, accurate assay to detect treosulfan and fludarabine simultaneously in human plasma using turbulent flow liquid chromatography coupled to electrospray ionization tandem mass spectrometry (TFLC-ESI-MS/MS). Treosulfan and fludarabine are extracted from only 100 μL of acidified plasma via protein precipitation with methanol containing isotope-labeled internal standards. The extract is injected into the TFLC-ESI-MS/MS system, and the analytes are quantified using multiple reaction monitoring and a six-point calibration curve.
    Keywords:  Fludarabine; Mass spectrometry; Method validation; Plasma; Therapeutic drug monitoring; Treosulfan; Turbulent flow liquid chromatography
    DOI:  https://doi.org/10.1007/978-1-0716-3541-4_42
  35. Clin Chem Lab Med. 2023 Nov 28.
       OBJECTIVES: Primary aldosteronism is the most common cause of endocrine hypertension and is associated with significant cardiovascular morbidities. The diagnostic workup depends on determinations of plasma aldosterone and renin which are highly variable and associated with false-positive and false-negative results. Quantification of aldosterone in 24 h urine may provide more reliable results, but the methodology is not well established. We aimed to establish an assay for urinary aldosterone and related steroids with suitability for clinical routine implementation.
    METHODS: Here, we report on the development and validation of a quantitative LC-MS/MS method for six urinary steroids: aldosterone, cortisol, 18-hydroxycorticosterone, 18-hydroxycortisol, 18-oxocortisol, tetrahydroaldosterone. After enzymatic deconjugation, total steroids were extracted using SepPak tC18 plates and quantified in positive electrospray ionization mode on a QTRAP 6500+ mass spectrometer.
    RESULTS: Excellent linearity was demonstrated with R2>0.998 for all analytes. Extraction recoveries were 89.8-98.4 % and intra- and inter-day coefficients of variations were <6.4 and <9.0 %, establishing superb precision. Patients with primary aldosteronism (n=10) had higher mean 24 h excretions of aldosterone-related metabolites than normotensive volunteers (n=20): 3.91 (95 % CI 2.27-5.55) vs. 1.92 (1.16-2.68) µmol/mol for aldosterone/creatinine, 2.57 (1.49-3.66) vs. 0.79 (0.48-1.10) µmol/mol for 18-hydroxycorticosterone/creatinine, 37.4 (13.59-61.2) vs. 11.61 (10.24-12.98) µmol/mol for 18-hydroxycortisol/creatinine, 1.56 (0.34-2.78) vs. 0.13 (0.09-0.17) µmol/mol for 18-oxocortisol/creatinine, and 21.5 (13.4-29.6) vs. 7.21 (4.88-9.54) µmol/mol for tetrahydroaldosterone/creatinine.
    CONCLUSIONS: The reported assay is robust and suitable for routine clinical use. First results in patient samples, though promising, require clinical validation in a larger sample set.
    Keywords:  aldosterone; mass spectrometry; method validation; primary aldosteronism; urinary steroids
    DOI:  https://doi.org/10.1515/cclm-2023-0250
  36. Anal Biochem. 2023 Nov 26. pii: S0003-2697(23)00370-6. [Epub ahead of print]685 115405
      Acetyl-Coenzyme A is a central metabolite in catabolic and anabolic pathways as well as the acyl donor for acetylation reactions. Multiple quantitative measurement techniques for acetyl-CoA have been reported, including commercially available kits. Comparisons between techniques for acetyl-CoA measurement have not been reported. This lack of comparability between assays makes context-specific assay selection and interpretation of results reporting changes in acetyl-CoA metabolism difficult. We compared commercially available colorimetric ELISA and fluorometric enzymatic-based kits to liquid chromatography-mass spectrometry-based assays using tandem mass spectrometry (LC-MS/MS) and high-resolution mass spectrometry (LC-HRMS). The colorimetric ELISA kit did not produce interpretable results even with commercially available pure standards. The fluorometric enzymatic kit produced comparable results to the LC-MS-based assays depending on matrix and extraction. LC-MS/MS and LC-HRMS assays produced well-aligned results, especially when incorporating stable isotope-labeled internal standards. In addition, we demonstrated the multiplexing capability of the LC-HRMS assay by measuring a suite of short-chain acyl-CoAs in a variety of acute myeloid leukemia cell lines and patient cells.
    Keywords:  Acetyl-CoA; Mass spectrometry; Metabolite; Method comparison
    DOI:  https://doi.org/10.1016/j.ab.2023.115405
  37. J AOAC Int. 2023 Dec 01. pii: qsad127. [Epub ahead of print]
       BACKGROUND: The consumption of foods containing amphenicols, a type of antibiotic, is a major concern for human health. A stable and accurate detection method can provide technical support for the food-safety monitoring.
    OBJECTIVE: An effective and efficient method was established for determining amphenicols in animal-derived foods through the simultaneous use of solid-phase extraction (SPE) cleanup and ultra-high-performance liquid chromatography/mass spectrometry (UPLC-MS/MS).
    METHOD: Samples were extracted using 1.0% ammoniated ethyl acetate solution, degreased with n-hexane, and then concentrated and cleaned using a C18 SPE column. Next, gradient elution was performed using methanol and 0.05% aqueous ammonia as the mobile phase, followed by separation using a C18 column. The target compound was detected using electrospray ionisation, both in positive and negative modes, through multiple reaction monitoring, and quantified using an internal-standard method.
    RESULTS: The content of chloramphenicol (CAP), florfenicol (FF) and florfenicol amine (FFA) (content range: 0.2-8.0 µg/kg) as well as that of thiamphenicol (TAP; content range: 1.0-40.0 µg/kg) show a good linear relationship, with a correlation coefficient of r > 0.999. Furthermore, recoveries of 86.7%-111.9% and relative standard deviations of < 9.0% were achieved. The limits of detection and quantification are obtained as 0.03-0.33 and 0.1-1.0 μg/kg, respectively.
    CONCLUSION: The proposed method has excellent stability and accuracy, and can be successfully used for the qualitative and quantitative determination of amphenicols, i.e., CAP, TAP, FF and FFA residues in 210 animal-derived food samples, of which FF and FFA were detected in four samples.
    HIGHLIGHTS: A stable and accurate method was successfully established for the simultaneous determination of CAP, TAP, FF and FFA in animal-derived foods using UPLC-MS/MS. Effective sample pretreatment was established, lipids were removed using n-hexane, concentration and cleanup were achieved with the C18 SPE column, and matrix effects were effectively reduced, thus improving the method's accuracy and stability. The method was validated for eight common animal-source foods, including beef, lamb, pork, chicken, egg, milk, fish and honey. This method has good applicability for CAP, TAP, FF and FFA in animal-derived foods.
    DOI:  https://doi.org/10.1093/jaoacint/qsad127
  38. J Pharm Biomed Anal. 2023 Nov 28. pii: S0731-7085(23)00654-4. [Epub ahead of print]239 115885
      Trifluridine (FTD) and tipiracil (TPI) hydrochloride tablets (TAS-102) were used for the treatment of patients with metastatic rectal cancer that was resistant to conventional chemotherapy drugs. In this study, a rapid and sensitive liquid chromatography-tandem mass spectrometry method was developed and fully validated for the simultaneous determination of TPI, FTD, and the metabolite 5-trifluoromethyluracil (FTY) of FTD in human plasma. The plasma samples were prepared by protein precipitation. The chromatography separation was performed using ACE Excel 3 AQ (100 × 2.1 mm i.d., 1.7 µm, ACE, England) column protected by a security guard cartridge (4.0 × 2.0 mm i.d., 5 µm, Phenomenex, USA) with a gradient elution of 0.05% acetic acid in water and methanol at a flow rate of 0.35 mL/min. The MS/MS analysis was performed by using multiple reaction monitoring with the segmented polarity (positive for TPI: m/z 243.1→183.0, and negative for FTD: m/z 295.1→252.0 and FTY: m/z 178.9→158.9) electrospray ionization mode. The segmented polarity mode was designed to achieve two advantages: better sensitivity and simultaneous determination of the analytes with different ion polarities. The calibration ranges were as follows: 1.00-250 ng/ for TPI, 8.00-8000 ng/mL for FTD and 5.00-1250 ng/mL for FTY. The selectivity, accuracy, precision, matrix effect, recovery, carryover, dilution integrity and stability test results meet ICH acceptance criteria. The method was evaluated using the RGB model and successfully applied to a clinical study in patients with solid tumors. For TPI, FTD and FTY, the maximum plasma concentration was 137-147 ng/mL, 6160-6240 ng/mL and 724-725 ng/mL, respectively; the plasma elimination half-life was 1.69-1.78 h, 1.70 h, and 3.09-3.14 h, respectively, after an oral administration of 60 mg TAS-102.
    Keywords:  5-trifluoromethyluracil; Assay; LC-MS/MS; Segmented polarity; Tipiracil; Trifluridine
    DOI:  https://doi.org/10.1016/j.jpba.2023.115885
  39. Methods Mol Biol. 2024 ;2737 423-433
      N,N',N''-Triethylenethiophosphoramide (thioTEPA) is a polyfunctional, organophosphorus alkylating agent that has been a primary treatment of multiple solid malignancies for many years and more recently as part of conditioning regimens prior to hematopoietic stem cell transplantation for a variety of hematologic malignancies. In vivo, thioTEPA is quickly metabolized to N,N',N″-triethylenephosphoramide (TEPA). ThioTEPA and TEPA have similar alkylating activity and both exhibit outstanding central nervous system penetration. Therefore, it is possible and desirable to monitor both compounds in plasma and cerebrospinal fluid (CSF).This chapter describes a method to measure both compounds simultaneously. ThioTEPA and TEPA are extracted with solvent from plasma and CSF by the addition of deuterated internal standards prepared in methanol. Chromatographic separation is attained using a C18 column and mass spectrometry which is performed in the positive ion mode. Herein, we describe a fast, accurate, and sensitive assay to quantify both compounds in plasma and CSF by turbulent flow LC-MS/MS which allows for fast and accurate therapeutic drug monitoring and timely dose modifications.
    Keywords:  CSF; Mass spectrometry; Method validation; Pharmacokinetics; Plasma; TEPA; Turbulent flow liquid chromatography; thioTEPA
    DOI:  https://doi.org/10.1007/978-1-0716-3541-4_39
  40. Biomed Chromatogr. 2023 Dec 01. e5789
      A method using ultrahigh-performance liquid chromatography-tandem mass spectrometry was developed, validated, and applied to simultaneously determine plasma methotrexate (MTX) and 7-hydroxy-methotrexate (7-OH-MTX) in 117 patients with central nervous system (CNS) lymphoma. The ion transitions utilized were m/z 455.2 > 308.2 for MTX and m/z 471.2 > 324.1 for 7-OH-MTX. Samples were prepared through protein precipitation using methanol. Chromatographic separation was achieved within 3.0 min on a CMS9030 column (Ruixi, 2.1 × 50 mm, 3 μm) through a gradient elution of methanol and a 10% ammonium acetate solution at a flow rate of 0.4 mL/min. The method demonstrated linearity in the concentration range of 0.05-10 μM for MTX and 0.25-50 μM for 7-OH-MTX. The intra- and inter-day inaccuracy ranged from -7.38% to 7.83%, and the imprecision was less than 6.00% for both analytes. The recovery and matrix effect normalized by the internal standard (MTX-D3 ) remained consistent. Both analytes remained stable under nine different storage conditions. In patients with CNS lymphoma, MTX levels at 12 h and 7-OH-MTX levels at 12, 36, and 60 h after dosing in individuals with impaired renal function were significantly higher compared with those with normal renal function. 7-OH-MTX could potentially serve as a superior indicator for nephrotoxicity compared with MTX.
    Keywords:  7-hydroxy-methotrexate; UHPLC-MS/MS; method development and validation; methotrexate; renal impairment
    DOI:  https://doi.org/10.1002/bmc.5789
  41. Methods Mol Biol. 2024 ;2737 435-442
      The Cannabis plant has been smoked for medicinal and recreational purposes for thousands of years. Tetrahydrocannabinol (THC) is the most well-known psychoactive cannabinoid, and the properties of other cannabinoids are becoming better understood. Due to increased exposure, hospitals and clinics will need access to rapid and accurate THC testing procedures to better inform patients and improve care. A rapid and reliable HPLC-MS/MS method was developed for the quantitative assessment of two THC metabolites (THC-COOH and THC-COO(Gluc)). The chromatographic separation was done using a short (50 × 4.6 mm) phenyl-hexyl column with positive ESI mass spectrometry analysis. To reduce interferences and improve quantitation, the assay was run using multiple reaction monitoring mode. The method was shown to be precise (<15% CV with-in day & between day), accurate (±20%) and linear (>R2 0.99) within the range of 25-8000 ng/mL.
    Keywords:  Dilute-and-shoot; HPLC-MS/MS; Quantitation; THC; Toxicology; Urine
    DOI:  https://doi.org/10.1007/978-1-0716-3541-4_40
  42. Front Nutr. 2023 ;10 1229445
      Vitamin D is essential for optimal bone health, and vitamin D deficiency has been associated with an increased risk of adverse pregnancy, growth and developmental outcomes. In early life, and in the absence of endogenous vitamin D production from UVB light, infants are reliant on vitamin D stores established in utero and the vitamin D supply from human milk (HM). However, comprehensive data on vitamin D in HM is lacking. Thus, in this review we explore the application of liquid-chromatography tandem mass spectrometry (LC-MS/MS) to the assessment of vitamin D in HM. We discuss the challenges of extracting and measuring multiple vitamin D metabolites from HM including the frequent requirement for a large sample volume, and inappropriate poor sensitivity. Shortcomings in the reporting of experimental procedures and data analysis further hinder advances in the field. Data collated from all studies that have applied LC-MS/MS reveal that, in general, cholecalciferol concentration is greater and more variable than 25-hydroxyvitamin D concentration, and that the vitamin D content of HM is low and less than the currently recommended dietary requirement of infants, although maternal supplementation can increase the vitamin D content of HM. Improvements in analytical methods and their validation and larger, more representative studies are required to better characterize HM milk vitamin D metabolite concentrations and their relationship with maternal status. These data are essential to understand relationships with infant health and to inform public health policies around vitamin D fortification and supplementation.
    Keywords:  25-hydroxyvitamin D; breast milk; infant feeding; mass spectrometry; vitamin D
    DOI:  https://doi.org/10.3389/fnut.2023.1229445
  43. Methods Mol Biol. 2024 ;2737 33-41
      Epilepsy is characterized by abnormal electrical discharges in the brain that result in unprovoked seizures. Pharmacotherapy with antiepileptic drugs (AED) can help control the incidence of epileptic seizures. AED therapeutic regimens often need to be individually tailored. Therapeutic drug monitoring (TDM) of AED is required to optimize therapeutic efficacy and minimize the risk of any associated destructive toxicities. We describe a turbulent flow liquid chromatography-tandem mass spectrometry (TFC-MS/MS) method for the detection of seven different AED in human serum. TFC-MS/MS testing was performed using a TLX-2 online sample preparation liquid chromatography (SPLC) system coupled to an API 5500 Q-Trap tandem mass spectrometer. Quantification of 10,11-dihydro-10-hydroxycarbamazepine, lacosamide, lamotrigine, levetiracetam, rufinamide, topiramate, and zonisamide was, respectively, performed using calibration curves (2-60 μg/mL, R2 > 0.99) with precisions of <10%.
    Keywords:  Antiepileptic drugs; Atmospheric pressure chemical ionization; Serum; Therapeutic drug monitoring; Turbulent flow liquid chromatography-tandem mass spectrometry
    DOI:  https://doi.org/10.1007/978-1-0716-3541-4_4