Online electrochemistry/mass spectrometry in drug metabolism studies: principles and applications.

IMPORTANCE OF THE FIELD Conventional metabolism studies in early stages of drug development include in vitro tests, often based on hepatic cells and cell extracts, as well as in vivo tests on the basis of animal models. Complementary to these existing techniques, the electrochemical study of oxidative metabolism reactions is gaining increasing attention. Electrochemistry (EC) allows the fast detection of sites labile towards oxidation in a drug molecule and can mimic the formation of potential oxidative metabolites. AREAS COVERED IN THIS REVIEW The present review summarizes the developments of EC-based methods to study the oxidative metabolism of drugs in the past 10 years. The implementation of different coulometric and amperometric cells is described. Furthermore, online set-ups utilizing the hyphenation of EC, liquid chromatography and electrospray ionization mass spectrometry are discussed regarding their applicability in metabolism studies. Besides mass spectrometric detection, the isolation and advanced characterization of oxidation products are reviewed. This includes structure elucidation based on NMR spectroscopy as well as the evaluation of the reactivity of metabolites towards trapping agents or proteins. WHAT THE READER WILL GAIN A major focus of the article is directed to the comparability between electrochemically predicted metabolites and those occurring in vitro and in vivo. This comprises the discussion of typical oxidative metabolism reactions and provides a guideline about how far EC is capable of generating a specific oxidative metabolite. TAKE HOME MESSAGE The study of drug metabolism reactions in an electrochemical cell enables the prediction as well as the synthesis of oxidative metabolites. In particular, reactive metabolites are directly detected using online EC/electrospray ionization mass spectrometry. Thus, the electrochemical technique is a promising tool that complements existing in vivo and in vitro techniques in drug metabolism studies.