Metabolism of a potential 8-aminoquinoline antileishmanial drug in rat liver microsomes

Biochem Pharmacol. 1985 Jan 15;34(2):181-8. doi: 10.1016/0006-2952(85)90122-4.


The metabolism of the 8-aminoquinoline, 8-(6-diethylaminohexylamino)-6-methoxy-lepidine dihydrochloride (WR 6026 X 2HCl), was studied in a rat hepatic microsomal system. The results show that WR 6026 X 2HCl was metabolized into two more polar compounds. The structures of these metabolites as proven by gas chromatography-mass spectrometry, ultraviolet absorption, and high performance liquid chromatography were: 8-(6-ethylaminohexylamino)-6-methoxy-lepidine (metabolite 1) and 8-(6-diethylaminohexylamino)-6-methoxy-4-hydroxymethyl quinoline (metabolite 2). The formation of both metabolites was NADPH dependent and also linearly dependent on incubation time and microsomal protein concentration at 0.24 mM WR 6026 X 2 HCl. Studies on the effects of pretreatment of animals with either phenobarbital or Aroclor 1254 suggest that cytochrome P-450 isozymes catalyzed both N-deethylation and hydroxylation reactions. N-deethylase activity was induced by either pretreatment: however, hydroxylase activity was unaffected by phenobarbital pretreatment and significantly elevated by Aroclor 1254 pretreatment. These results suggest that these two reactions are catalyzed by different cytochrome P-450 isozymes. The formation of these two metabolites in vivo may play an important role in the antileishmanial activity of WR 6026 X 2HCl.

MeSH terms

  • Aminoquinolines / metabolism*
  • Animals
  • Antiprotozoal Agents / metabolism*
  • Enzyme Induction / drug effects
  • In Vitro Techniques
  • Leishmania / drug effects*
  • Male
  • Mass Spectrometry
  • Microsomes, Liver / metabolism*
  • Polychlorinated Biphenyls / pharmacology
  • Rats
  • Rats, Inbred Strains


  • Aminoquinolines
  • Antiprotozoal Agents
  • Polychlorinated Biphenyls
  • 8-aminoquinoline