Mechanisms of trovafloxacin hepatotoxicity: studies of a model cyclopropylamine-containing system

Bioorg Med Chem Lett. 2007 Dec 15;17(24):6682-6. doi: 10.1016/j.bmcl.2007.10.070. Epub 2007 Oct 24.

Abstract

The mechanism for the hepatotoxicity of trovafloxacin remains unresolved. Trovafloxacin contains a cyclopropylamine moiety which has a potential to be oxidized to reactive intermediate(s) although other putative elements may exist. In this study, a drug model of trovafloxacin containing the cyclopropylamine substructure was synthesized. Chemical oxidation of the drug model by K(3)Fe(CN)(6) and NaClO revealed that both oxidants oxidize this drug model to a reactive alpha,beta-unsaturated aldehyde, 11. The structure of 11 was fully elucidated by LC/MS/MS and NMR analysis. These results suggested that P450s with heme-iron center and myeloperoxidase generating hypochlorous acid in the presence of chloride ion are capable of bioactivating the cyclopropylamine moiety of trovafloxacin. This deleterious metabolism may lead to eventual hepatotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes / chemistry
  • Chromatography, Liquid
  • Cyclopropanes / chemical synthesis
  • Cyclopropanes / chemistry*
  • Cyclopropanes / toxicity*
  • Fluoroquinolones / chemistry*
  • Fluoroquinolones / toxicity*
  • Liver / drug effects*
  • Magnetic Resonance Spectroscopy
  • Models, Biological*
  • Molecular Structure
  • Naphthyridines / chemistry*
  • Naphthyridines / toxicity*
  • Oxidation-Reduction

Substances

  • Aldehydes
  • Cyclopropanes
  • Fluoroquinolones
  • Naphthyridines
  • cyclopropylamine
  • trovafloxacin