Interpretation of tandem mass spectra of antiepileptic drugs using accurate-m/z data and m/z-shifts with stable-isotope labeled analogues

Anticonvulsant or antiepileptic drugs (AEDs) show a great structural diversity. Often, therapeutic drug monitoring (TDM) based on liquid chromatography–(tandem) mass spectrometry is applied to (individually) optimize the treatment of epilepsy and to prevent seizures. To this end, tandem-quadrupole instruments are operated in selected-reaction monitoring (SRM) mode, using one or more structure-specific product ions for the detection and quantification of the AEDs. In this study, the fragmentation in tandem mass spectrometry (MS–MS) of more than 30 antiepileptic drugs as well as more than 30 (pharmacologically relevant) metabolites is reviewed. Information on fragmentation that is scattered in the scientific literature is collected and interpreted. The identity of product ions used in SRM, i.e., elemental composition and exact-m/z, is tabulated, and more detailed fragmentation schemes and structure proposals for product ions are provided. In this way, insight is gained in the identity of the product ions used in SRM, which is a topic that is often ignored in the development of TDM methods. Moreover, this review helps in strengthening our understanding of the small-molecule fragmentation in MS–MS. In the case of AEDs, the structure proposals for the product ions can not only be confirmed with accurate-m/z data from high-resolution MS instruments, but also by studying m/z-shifts of products ions of the stable-isotope labeled analogues, that are frequently used as internal standard. For some compounds, this gives insight in the skeletal rearrangements occurring in the formation of some product ions.