Metabolism of a potential 8-aminoquinoline antileishmanial drug in rat liver microsomes.
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.
D000634:Aminoquinolines / Q000378:metabolism*; D000818:Animals; D000981:Antiprotozoal Agents / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D066298:In Vitro Techniques; D007891:Leishmania / Q000187:drug effects*; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism*; D011078:Polychlorinated Biphenyls / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D000634:Aminoquinolines; D000981:Antiprotozoal Agents; D011078:Polychlorinated Biphenyls; C080436:8-aminoquinoline