Production of a reactive metabolite of troglitazone by electrochemical oxidation performed in nonaqueous medium

Kayoko Tahara, Takashi Nishikawa, Yutaka Hattori, Shiro Iijima, Yukiko Kouno, Yoshihiro Abe

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

In order to confirm the existence of reactive metabolites by LC-MS/MS analysis, they should be modified into stable compounds, because some reactive metabolites generated by biotransformation induce drug toxicity; however, they are unstable, with very short lives, and cannot be detected in their intact forms. To overcome these problems, electrochemical oxidation of troglitazone was performed in nonaqueous medium, since such reactive compounds are stable in the absence of water. Troglitazone, an antidiabetic agent, was withdrawn from the market because of serious hepatotoxicity in some patients. It has been considered that one or more reactive metabolites are involved in hepatotoxicity, although the mechanism of the adverse reaction is unclear. Using our method of electrochemical oxidation in nonaqueous medium, we obtained a product of troglitazone derivative that may be a clue to clarify the mechanism of toxicity. The product in the reaction mixture was separated by HPLC without chemical modification and detected using UV and ESI-MS. The mass spectrum of its molecular ion showed that it was an o-quinone methide derivative of troglitazone and identified as a reactive metabolite generated by liver microsome oxidation of the drug. The product was stable over 24 h at room temperature in anhydrous acetonitrile, but it reacted with N-(tert-butoxycarbonyl)-l-cystein methylester to produce an adduct that could be identified by its m/z value. Thus, the method of electrochemical oxidation in nonaqueous medium is considered to be useful to prepare and predict reactive metabolites of drugs that are unstable in aqueous medium or in vivo.

Original languageEnglish
Pages (from-to)1030-1036
Number of pages7
JournalJournal of Pharmaceutical and Biomedical Analysis
Volume50
Issue number5
DOIs
Publication statusPublished - 2009 Dec 5

Keywords

  • Electrochemical oxidation
  • LC-MS
  • Nonaqueous medium
  • Reactive drug metabolite
  • Troglitazone

ASJC Scopus subject areas

  • Analytical Chemistry
  • Pharmaceutical Science
  • Drug Discovery
  • Spectroscopy
  • Clinical Biochemistry

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