Differences in the metabolism of the antitumour agents amsacrine and its derivative CI-921 in rat and mouse

Xenobiotica. 1992 Jun;22(6):657-69. doi: 10.3109/00498259209053128.

Abstract

1. Rats and mice were treated with the antitumour agent CI-921 (I), and parent compound amsacrine, with all biliary metabolites being analysed. 2. In both rat and mouse the major biliary metabolites of amsacrine are the 5'- and 6'-glutathione (GSH) conjugates, with no C9-GSH conjugate being detected. 3. 5'- and 6'-GSH conjugates of I are also formed in both species. However, two additional products were detected and their structures confirmed by liquid secondary ion mass spectrometry and 1H-n.m.r. spectrometry, and by comparison with synthetic standards. 4. Additional metabolites of I are the C9-GSH conjugate and the 4-hydroxymethyl derivative which, either as the aglycone or glucuronide, is the predominant product in rat bile (comprising 56% of the dose eliminated over 3.5 h). 5. Relative amounts of the C9-GSH conjugate to the 5'- and 6'-GSH conjugates to the 4-hydroxymethyl derivatives, were 24:65:10 in mouse bile and 2:8:90 in rat bile. 6. These differences indicate first, likely enzyme involvement in the formation of the C9-GSH conjugate of I, and second, in comparison with amsacrine, alternative pathways which may decrease formation of the reactive quinone diimine intermediate of I and consequent hepatotoxicity.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amsacrine / analogs & derivatives*
  • Amsacrine / metabolism*
  • Amsacrine / urine
  • Animals
  • Antineoplastic Agents / metabolism*
  • Antineoplastic Agents / urine
  • Bile / chemistry
  • Chromatography, High Pressure Liquid
  • Kinetics
  • Mice
  • Rats

Substances

  • Antineoplastic Agents
  • Amsacrine
  • asulacrine