title: Combination of electrochemistry and nuclear magnetic resonance spectroscopy for metabolism studies.
abstract: During the development of new materials demonstrating biological activity, prediction and identification of reactive intermediates generated in the course of drug metabolism in the human liver is of great importance. We present a rapid and purely instrumental method for the structure elucidation of possible phase I metabolites. With electrochemical (EC) conversion adopting the oxidative function of liver-inherent enzymes and nuclear magnetic resonance (NMR) spectroscopy enabling structure elucidation, comprehensive knowledge on potential metabolites can be gained. Paracetamol (APAP) has been known to induce hepatotoxicity when exceeding therapeutic doses and was therefore selected as the test compound. The reactive metabolite N-acetyl-p-benzoquinone imine has long been proven to be responsible for the toxic side effects of APAP and can easily be generated by EC. EC coupled online to NMR is a straightforward technique for structure elucidation of reactive drug intermediates at an early stage in drug discovery.
authors.affiliation: Institut für Anorganische und Analytische Chemie, Westfälische Wilhelms-Universität Münster, Corrensstrasse 30, 48149 Münster, Germany.
authors.forename: Hannah
authors.initials: H
authors.lastname: Simon
authors.forename: Daniel
authors.initials: D
authors.lastname: Melles
authors.forename: Sandrine
authors.initials: S
authors.lastname: Jacquoilleot
authors.forename: Paul
authors.initials: P
authors.lastname: Sanderson
authors.forename: Raniero
authors.initials: R
authors.lastname: Zazzeroni
authors.forename: Uwe
authors.initials: U
authors.lastname: Karst
mesh_terms: D000082:Acetaminophen / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D018712:Analgesics, Non-Narcotic / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D016227:Benzoquinones / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D004353:Drug Evaluation, Preclinical / Q000191:economics / Q000295:instrumentation; D055664:Electrochemical Techniques / Q000191:economics / Q000295:instrumentation*; D004867:Equipment Design; D006801:Humans; D007097:Imines / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D009682:Magnetic Resonance Spectroscopy / Q000191:economics / Q000295:instrumentation*; D010084:Oxidation-Reduction
chemical_list: D018712:Analgesics, Non-Narcotic; D016227:Benzoquinones; D007097:Imines; D000082:Acetaminophen; C028473:N-acetyl-4-benzoquinoneimine