title: The bioactivation of amodiaquine by human polymorphonuclear leucocytes in vitro: chemical mechanisms and the effects of fluorine substitution.
abstract: Amodiaquine, a 4-aminoquinoline antimalarial, has been associated with hepatitis and agranulocytosis in humans. Drug hypersensitivity reactions, especially agranulocytosis, have been attributed to reactive intermediates generated by the oxidants discharged from stimulated polymorphonuclear leucocytes (PMN). The metabolism of amodiaquine to both stable and chemically reactive metabolites by human PMN has been investigated in vitro. Incubation of [14C]-amodiaquine with PMN resulted in irreversible binding of radiolabel to protein and depletion of intracellular reduced glutathione, which were enhanced by phorbol myristate acetate (PMA), a PMN activator. Two metabolites were identified: the C-5' glutathione adduct of amodiaquine, derived from both endogenous and exogenous glutathione, and 4-amino-7-chloroquinoline, which was presumed to be formed by hydrolysis of amodiaquine quinoneimine. Desethylamodiaquine, the major plasma metabolite of amodiaquine in humans, also underwent bioactivation to a chemically reactive species in the presence of PMA-stimulated PMN. Substitution of the 4'-hydroxyl group in amodiaquine with fluorine significantly reduced irreversible binding to protein and abolished depletion of intracellular glutathione in the presence of PMA. These findings indicate that the bioactivation of amodiaquine by PMN is associated with the formation of a quinoneimine intermediate. Such a reactive metabolite, if produced in PMN or bone marrow in vivo, may be responsible for the drug's myelotoxicity.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Liverpool, U.K.
authors.forename: M D
authors.initials: MD
authors.lastname: Tingle
authors.forename: H
authors.initials: H
authors.lastname: Jewell
authors.forename: J L
authors.initials: JL
authors.lastname: Maggs
authors.forename: P M
authors.initials: PM
authors.lastname: O'Neill
authors.forename: B K
authors.initials: BK
authors.lastname: Park
mesh_terms: D000655:Amodiaquine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D000962:Antimalarials / Q000378:metabolism*; D001711:Biotransformation; D005461:Fluorine / Q000737:chemistry; D005978:Glutathione / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D018375:Neutrophil Activation; D009504:Neutrophils / Q000378:metabolism*; D012709:Serum Albumin / Q000737:chemistry; D013755:Tetradecanoylphorbol Acetate
chemical_list: C094706:7-chloro-4-(4'-fluoro-5'-((diethylamino)methylanilino))quinoline; D000962:Antimalarials; D012709:Serum Albumin; C094705:amodiaquine quinoneimine; D000655:Amodiaquine; D005461:Fluorine; C047386:desethylamodiaquine; D005978:Glutathione; D013755:Tetradecanoylphorbol Acetate