Institut für Anorganische und Analytische Chemie, Westfälische Wilhelms-Universität Münster, Corrensstrasse 30, 48149 Münster, Germany.
Anal Chem. 2012 Oct 16;84(20):8777-82. doi: 10.1021/ac302152a. Epub 2012 Sep 25.
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.
在开发具有生物活性的新材料的过程中，预测和识别人肝脏药物代谢过程中产生的反应性中间体非常重要。我们提出了一种快速而纯粹的仪器方法，用于阐明可能的 I 相代谢物的结构。采用电化学（EC）转化，利用肝内固有酶的氧化功能，结合核磁共振（NMR）光谱进行结构阐明，可以全面了解潜在的代谢物。扑热息痛（APAP）在超过治疗剂量时已知会引起肝毒性，因此被选为测试化合物。反应性代谢物 N-乙酰-p-苯醌亚胺长期以来一直被认为是 APAP 毒性副作用的原因，并且可以很容易地通过 EC 产生。EC 与 NMR 在线偶联是一种在药物发现的早期阶段阐明反应性药物中间体结构的简单技术。
