Preparative Microfluidic Electrosynthesis of Drug Metabolites

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ACS Med. Chem. Lett. 2013, 4 (11), pp 1119–1123

  • Romain Stalder and Gregory P. Roth
  • Sanford-Burnham Medical Research Institute at Lake Nona, 6400 Sanger Road, Orlando, FL 32827, USA

This paper describes the preparative electrochemical synthesis of phase I and phase II metabolites of a range of commercial drug molecules. In this study the Flux module is utilised to replicate hepatic oxidation, whilst maintaining high throughput at the preparative scale (100mg/hr) generating a range of phase I metabolites and Phase II Glutathione adducts on a range of commercially available drug molecules, therefore enabling full structural elucidation of these metabolites to be carried out by NMR (1D and 2D).

Abstract: In vivo, a drug molecule undergoes its first chemical transformation within the liver via CYP450-catalyzed oxidation. The chemical outcome of the first pass hepatic oxidation is key information to any drug development process. Electrochemistry can be used to simulate CYP450 oxidation, yet it is often confined to the analytical scale, hampering product isolation and full characterization. In an effort to replicate hepatic oxidations, while retaining high throughput at the preparative scale, microfluidic technology and electrochemistry are combined in this study by using a microfluidic electrochemical cell. Several commercial drugs were subjected to continuous-flow electrolysis. They were chosen for their various chemical reactivity: their metabolites in vivo are generated via aromatic hydroxylation, alkyl oxidation, glutathione conjugation, or sulfoxidation. It is demonstrated that such metabolites can be synthesized by flow electrolysis at the 10 to 100 mg scale, and the purified products are fully characterized.

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This paper use the Asia Flux module on an Asia system.