Metabolic profiling of pharmaceuticals
Metabolism is the enzymatic conversion of one chemical compound into another (= metabolite). During metabolic transformation, polar bodies are either introduced or unmasked, which results in (more) polar metabolites of the original chemicals. The modification of xenobiotics facilitates their removal from the body. When metabolites are pharmacologically inert, metabolism deactivates the administered dose of parent drug and this usually reduces the effects on the body. Metabolites may also be pharmacologically active, sometimes more so than the parent drug.
Beside other techniques, mass spectrometry (MS) plays an invaluable role in the elucidation of biotransformation pathways of drugs by identifying circulatory and excretory metabolites. Especially liquid chromatography (LC) hyphenated to electrospray ionization (ESI) MS has become a powerful tool for the rapid detection, structure elucidation, and quantification of drug-derived species within various biological specimens. LC enables the cleanup and fraction of compounds prior to mass spectrometric analysis. Thus, adverse effects on the mass spectrometric detectability of metabolites caused by matrix are reduced. Furthermore, based on varying chromatographic properties LC can be used to separate and thus to identify isomeric species. MS can be operated in different scan modes. For targeted approaches varying combinations of product ion, precursor ion and neutral loss scans are applied to screen a sample for predicted metabolic transformation products. Targeted analysis is specific and sensitive, but suffers from the problem that uncommon or unexpected transformation pathways might be ignored. Full scan MS represents a more versatile acquisition strategy which should enable the detection of most ionisable metabolites. Low- and high-resolution MS can be applied for the detection of transformation products by analyzing test and control samples. For structure elucidation of tentative metabolites full scan tandem mass spectrometric (MS/MS) data is acquired and interpreted.
The following publications provide examples for the successful application of our analytical expertise to scientific studies:
- Baumann, A., Lohmann, W., Schubert, B, Oberacher, H., Karst, U.
Metabolic Studies of Tetrazepam Based on Electrochemical Simulation in Comparison to In Vivo and In Vitro Methods
Journal of Chromatography A, 1216 (2009), 3192-3198.
- Schubert, B., Pavlic, M., Libiseller, K., Oberacher, H.
Unraveling the Metabolic Transformation of Tetrazepam to Diazepam with Mass Spectrometric Methods
Analytical and Bioanalytical Chemistry, 392 (2008), 1299-1308.