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Preliminary Communication

Practical aspect of dimer adduct formation in small-molecule drug analysis with LC-MS/MS

    Marek Dziadosz

    *Author for correspondence: Tel.: +49 511 532 4558;

    E-mail Address: Dziadosz.Marek@mh-hannover.de

    Institute of Legal Medicine, Hannover Medical School (MHH), Carl-Neuberg-Str. 1, D-30625, Hannover, Germany

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    ,
    Michael Klintschar

    Institute of Legal Medicine, Hannover Medical School (MHH), Carl-Neuberg-Str. 1, D-30625, Hannover, Germany

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    &
    Jörg Teske

    Institute of Legal Medicine, Hannover Medical School (MHH), Carl-Neuberg-Str. 1, D-30625, Hannover, Germany

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    Published Online:8 Nov 2021https://doi.org/10.4155/bio-2021-0165

    Abstract

    Aim: Since the MS/MS based detection of small-molecule drugs with poor or even no ion fragmentation is a challenge in bioanalysis, alternative MS/MS detection strategies were in focus of this study and applied in the field of forensic toxicology. Material & methods: Analyte quantification with liquid chromatography-tandem mass spectrometry of problematic drugs was studied by the application of dimer adduct formation and valproic acid (VPA) was used as a model drug. VPA adduct ions could be identified during infusion experiments and the VPA dimer adduct ion was optimized for the detection. Conclusion: Dimer adduct ion formation can be used as an effective way of VPA quantification in human serum. Further, the parallel detection of dimer adduct ions with other adduct ion types can be stated as advantage in LC-MS/MS analysis of problematic drugs.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Seger C, Salzmann L. After another decade: LC-MS/MS became routine in clinical diagnostics. Clin. Biochem. 82, 2–11 (2020).
      Medline CASGoogle Scholar
    • 2. Grebe SKG, Singh R. LC-MS/MS in the clinical laboratory – where to from here?. Clin. Biochem. Rev. 32, 5–31 (2011).
      MedlineGoogle Scholar
    • 3. Pitt JJ. Principles and applications of liquid chromatography-mass spectrometry in clinical biochemistry. Clin. Biochem. Rev. 30, 19–34 (2009).
      MedlineGoogle Scholar
    • 4. Dziadosz M. LC–MSn small-molecule drug analysis in human serum: could adducts have good prospects for therapeutic applications?. Bioanalysis 10, 371–373 (2018). • Summary of different adduct-based strategies applied for drug analysis.
      CASGoogle Scholar
    • 5. Dziadosz M. Influence of buffer concentration on electrospray ionization of γ-hydroxybutyrate adducts with the components of the mobile phase used in liquid chromatography–tandem mass spectrometry. J. Chromatogr. B 1008, 240–241 (2016).
      Medline CASGoogle Scholar
    • 6. Dziadosz M. Influence of sodium addition on taurine adduct formation generated in acetic acid/acetate salt buffer applied in LC–MS/MS analysis. J. Iran. Chem. Soc. 13, 1283–1287 (2016).
      CASGoogle Scholar
    • 7. Schug K, McNair HM. Adduct formation in electrospray ionization. Part 1: common acidic pharmaceuticals. J. Sep. Sci. 25, 759–766 (2002). • The formation of different adduct ions were discussed.
      Google Scholar
    • 8. Schug K, McNair HM. Adduct formation in electrospray ionization mass spectrometry II. Benzoic acid derivatives. J. Chromatogr. A 985, 531–539 (2003). • The formation of different adduct ions were discussed.
      Medline CASGoogle Scholar
    • 9. Kruve A, Kaupmees K. Adduct Formation in ESI/MS by mobile phase additives. J. Am. Soc. Mass Spectrom. 28, 887–894 (2017).
      Medline CASGoogle Scholar
    • 10. Pan H. A non-covalent dimer formed in electrospray ionization mass spectrometry behaving as a precursor for fragmentations. Rapid Commun. Mass Spectrom. 22, 3555–3560 (2008).
      Medline CASGoogle Scholar
    • 11. Baselt RC. Disposition of toxic drugs and chemicals in man. 10th Edition. Biomedical Publications, CA, USA (2014).
      Google Scholar
    • 12. Vlase L, Popa DS, Muntean D, Leucuta S. A new high-throughput LC-MS/MS assay for therapeutic level monitoring of valproic acid in human plasma. Sci. Pharm. 76, 663–672 (2008).
      CASGoogle Scholar
    • 13. Jain DD, Subbaiah G, Sanyal M, Shrivastav PA. A high throughput and selective method for the estimation of valproic acid an antiepileptic drug in human plasma by tandem LC–MS/MS. Talanta 72, 80–88 (2007).
      Medline CASGoogle Scholar
    • 14. Matsuura K, Ohmori T, Nakamura M, Itoh Y, Hirano KA. A simple and rapid determination of valproic acid in human plasma using a non-porous silica column and liquid chromatography with tandem mass spectrometric detection. Biomed. Chromatogr. 22, 387–393 (2008).
      Medline CASGoogle Scholar
    • 15. Gao S, Miao H, Tao X, Jiang B, Xiao Y, Cai F et al. LC-MS/MS method for simultaneous determination of valproic acid and major metabolites in human plasma. J. Chromatogr. B. 879, 1939–1944 (2011).
      Medline CASGoogle Scholar
    • 16. Kim KB, Seo KA, Kim SE, Bae SK, Kim DH, Shin JG. Simple and accurate quantitative analysis of ten antiepileptic drugs in human plasma by liquid chromatography/tandem mass spectrometry. J. Pharm. Biomed. Anal. 56, 771–777 (2011).
      Medline CASGoogle Scholar
    • 17. Shibata M, Hashi S, Nakanishi H, Masuda S, Katsura T, Yano I. Detection of 22 antiepileptic drugs by ultra-performance liquid chromatography coupled with tandem mass spectrometry applicable to routine therapeutic drug monitoring. Biomed. Chromatogr. 26, 1519–1528 (2012).
      Medline CASGoogle Scholar
    • 18. Cheng H, Liu Z, Blum W, Byrd JC, Klisovic R, Grever MR et al. Quantification of valproic acid and its metabolite 2-propyl-4-pentenoic acid in human plasma using HPLC-MS/MS. J. Chromatogr. B. 850, 206–212 (2007).
      Medline CASGoogle Scholar
    • 19. Dziadosz M, Klintschar M, Teske J. Small molecule adduct formation with the components of the mobile phase as a way to analyse valproic acid in human serum with liquid chromatography-tandem mass spectrometry. J. Chromatogr. B. 959, 36–41 (2014). •• Complementary VPA adduct based quantification method.
      Medline CASGoogle Scholar
    • 20. Dziadosz M. The application of multiple analyte adduct formation in the LC–MS3 analysis of valproic acid in human serum. J. Chromatogr. B. 1040, 159–161 (2017). •• Adduct based VPA quantification method with a MS3 detection.
      Medline CASGoogle Scholar
    • 21. Peters FT, Hartung M, Herbold M, Schmitt G, Daldrup T, Mußhoff F. Anhang B zur richtlinie der GTFCh zur qualitätssicherung bei forensisch-toxikologischen untersuchungen. Anforderungen an die validierung von analysenmethoden. Toxichem. Krimtech. 76, 185–208 (2009).
      Google Scholar
    • 22. Schulz M, Iwersen-Bergmann S, Andresen H, Schmoldt A. Therapeutic and toxic blood concentrations of nearly 1,000 drugs and other xenobiotics. Crit. Care. 16, R136 (2012).
      MedlineGoogle Scholar
    • 23. Matuszewski BK, Constanzer ML, Chavez-Eng CM. Strategies for the assessment of matrix effect in quantitative bioanalytical methods based on HPLC-MS/MS. Anal. Chem. 75, 3019–3030 (2003).
      Medline CASGoogle Scholar