Development of an electrochemical flow‐through cell for the fast and easy generation of isotopically labeled metabolite standards

Abstract

In drug development, metabolite standards of new chemical entities are required for a comprehensive safety evaluation. Stable isotope-labeled internal metabolite standards at the milligram scale, which are difficult and expensive to synthesize in common bottom-up approaches, are necessary for metabolite quantification using liquid chromatography/mass spectrometry. A preparative electrochemical flowthrough cell is presented here as a powerful tool for the cheap and straightforward synthesis of milligram amounts of isotopically labeled metabolite standards. The developed cell scales up established, so-called "coulometric" electrochemical cells.Problems like electrode fouling and cross contamination between syntheses are addressed by the use of exchangeable working electrodes. The applicability of the developed cell for the synthesis of metabolite standards is demonstrated using isotopically labeled acetaminophen as a model system for the generation of a biologically relevant phase II metabolite.

Electrochemistry coupled with mass spectrometry for the prediction of the environmental fate and elucidation of the degradation mechanisms of pesticides: current status and future prospects

“…42 On the other hand, the use of new ionization sources (APCI, Atmospheric Pressure Chemical Ionization, APPI, Atmospheric Pressure Photo Ionization, TIMS, Trapped Ion Mobility Spectrometry and MALDI, Matrix Assisted Laser Desorption Ionization) of mass spectrometry in the electrochemical simulation of metabolic processes is a promising route to explore. Proof of concept of some of these methods (EC/ESI-TIMS-ToF-MS and ESI/MALDI-TIMS-MS) was provided by Uwe Karst's team (Münster, Germany), 43,44 but further studies are required to demonstrate their applicability in oxidative/reductive simulation studies. APCI is complementary to ESI for less polar analytes and shows good sensitivity for compounds of intermediate molecular weight and polarity, while APPI is complementary to ESI and APCI for less polar analytes.…”

Microfluidic devices for photo-and spectroelectrochemical applications

“…A larger scale, automated setups, i.e. for the exposure of arrays of EC sensors [30] (see Figure 2e) and flowthrough EC cells for synthesis with exchangeable electrodes [31] are the examples of system level integration. Paper is a common material for EC-integrated microfluidics.…”

The Combination of Electrochemistry and Microfluidic Technology in Drug Metabolism Studies

“…[ 71 , 72 , 73 ] Conventional flow cells coupled to MS[ 75 , 76 , 77 , 78 , 79 , 80 ] have been used for the mimicry of drug metabolism and simulated successfully a range of oxidation reactions such as dehydrogenation, aromatic hydroxylation, heteroatom oxidation and N‐dealkylation. [ 81 , 82 ] Screen–printed electrodes have also been used for investigations in drug metabolism. [ 83 , 84 ] These are miniaturised and disposable electrode systems operating at ul levels.…”

“…Electrochemical methods are coupled with a suitable detection technique such as MS and complement the current preclinical techniques, saving time and cost [71–73] . Conventional flow cells coupled to MS [75–80] have been used for the mimicry of drug metabolism and simulated successfully a range of oxidation reactions such as dehydrogenation, aromatic hydroxylation, heteroatom oxidation and N‐dealkylation [81,82] . Screen–printed electrodes have also been used for investigations in drug metabolism [83,84] .…”