Name: Sandra Jahn
Diploma / M.Sc degree: Westfälische Wilhelms-Universität Münster, Germany
(February 2009)

PhD Project: Generation and Identification of Reactive Metabolites Using On-Line Electrochemistry/Liquid Chromatography/Mass Spectrometry


Homepage: http://www.uni-muenster.de/Chemie.ac/karst/group/jahn.html

Abstract of Research Project

The elucidation of the metabolic fate of drug candidates in the human body is one of the major challenges in pharmaceutical research. The main route of drug elimination is an enzymatic biotransformation taking place in the liver. It is frequently initiated by oxidation reactions ("phase I metabolism") which are catalyzed by enzymes of the cytochrome P450 superfamily. The resulting phase I metabolites are usually investigated with complex and time-consuming in vivo and in vitro experiments. Especially reactive metabolites, which play an important role when assessing the possible toxicity of new pharmaceuticals, are often difficult to detect. Hence, a rapid screening technique allowing for the provision of reliable and easily accessible information is required. This can be achieved using an electrochemical cell coupled on-line to liquid chromatography (LC) and electrospray ionization mass spectrometry (ESI-MS).

Electrochemical flow-through cells coupled on-line to analysis techniques such as ESI-MS with or without previous liquid chromatographic separation have nowadays become the technique of choice for these simulation experiments, since they may provide exhaustive information about the nature of the electrochemically generated metabolites. Particular interest lies in coupling reactions of the obtained reactive metabolites with trapping agents such as glutathione ("phase II metabolism") or even with cellular biomacromolecules like proteins. In first experiments, this approach has, for instance, been used for the simulation of the oxidative metabolism of the drugs verapamil and dobutamine. Recent work also includes the targeted trapping of reactive metabolites with metal-containing conjugation agents on the analytical and on the semi-preparative scale. It has already been demonstrated that the combination of electrochemistry, liquid chromatography and inductively coupled plasma-mass spectrometry is a powerful tool for the quantification of heteroatom-containing metabolites.

In summary, this project involves the on-line generation and identification of reactive metabolites and their reaction with trapping agents or proteins by a purely instrumental method.


Publications

S. Jahn, S. Beuck, I. Möller, M. Thevis, U. Karst
Using electrochemistry for metabolite simulation and synthesis in preventive doping research: application to the Rycal S107 and the PPARd-agonist GW1516
Anal. Methods 5 (2013), 1214-1224.

S. Jahn, B. Seiwert, S. Kretzing, G. Abraham, R. Regenthal, U. Karst
Metabolic Studies of the Amaryllidaceous Alkaloids Galantamine and Lycorine Based on Eletrochemical Simulaton in Addition to In Vivo and In Vitro Models
Anal. Chim. Acta 756 (2012), 60-72.

L. Telgmann, H. Faber, S. Jahn, D. Melles, H. Simon, M. Sperling, U. Karst
Identification and Quantification of Potential Metabolites of Gd-Based Contrast Agents by Electrochemistry/Separations/Mass Spectrometry
J. Chromatogr. A 1240 (2012), 147-155.

S. Jahn, R. Zazzeroni, H. Faber, U. Karst
Electrochemistry/Mass Spectrometry as a Tool in the Investigation of the Potent Skin Sensitizer p-Phenylenediamine and its Reactivity toward Nucleophiles
Rapid Commun. Mass Spectrom. 26 (2012), 1453-1464.

S. Jahn, R. Zazzeroni, H. Faber, U. Karst
Elecrochemistry/Liquid Chromatography/Mass Spectrometry to Demonstrate Irreversible Binding of the Skin Allergen p-Phenylenediamine to Proteins
Rapid Commun. Mass Spectrom. 26 (2012), 1415-1425.

S. Jahn, U. Karst
Electrochemistry/(Liquid Chromatography)/Mass Spectrometry – Current State and Future Perspectives
J. Chromatogr. A 1259 (2012), 16-49.

S. Jahn, W. Lohmann, S. Bomke, A. Baumann, U. Karst
A ferrocene-based reagent for the conjugation and quantification of reactive metabolites
Anal Bioanal Chem 402 (2012), 461–471.

H. Faber, S. Jahn, J. Künnemeyer, H. Simon, D. Melles, M. Vogel, U. Karst
Electrochemistry/Liquid Chromatography/Mass Spectrometry as a Tool in Metabolism Studies
Angew. Chem. Int. Ed. Engl. 50 (2011), A52-A58.

S. Jahn, A. Baumann, J. Roscher, K. Hense, R. Zazzeroni, U. Karst
Investigation of the biotransformation pathway of verapamil using electrochemistry/liquid chromatography/mass spectrometry – A comparative study with liver cell microsomes
J. Chromatogr. A 1218 (2011), 9210– 9220.

A. Baumann, W. Lohmann, S. Jahn, U. Karst
On-Line Electrochemistry/Electrospray Ionization Mass Spectrometry (EC/ESI-MS) for the Generation and Identification of Nucleotide Oxidation Products
Electroanalysis 22 (2010), 286-292.


Sandra Jahn
eMail: Sandra Jahn