title: The mechanism of bioactivation and antigen formation of amodiaquine in the rat.
abstract: A glutathione conjugate of amodiaquine has been isolated and characterized from rat bile after administration of [14C]amodiaquine (50 mumol/kg, 5.0 muCi/rat) to anaesthetized male Wistar rats. Thioether conjugates of amodiaquine in rat bile accounted for a total of 12% of the dose, 5 hr after administration of the drug. In addition, 1% of the dose remained in the liver covalently bound to tissue proteins after 5 hr. These findings provide direct evidence that a chemically reactive metabolite, amodiaquine quinoneimine, has been formed from the drug in vivo. A second major metabolite, desethylamodiaquine, accounting for 14% of the given dose, was present in the liver after 5 hr. Enzyme inhibition studies with ketoconazole-pretreated rats showed that both amodiaquine quinoneimine and desethylamodiaquine formation can be catalysed by cytochrome P450. The demonstration that amodiaquine readily and extensively forms a metabolite in vivo, with strong reactivity towards protein and non-protein thiol groups, may help to explain the idiosyncratic toxicity observed in man.
authors.affiliation: Department of Pharmacology and Therapeutics, Liverpool, U.K.
authors.forename: A C
authors.initials: AC
authors.lastname: Harrison
authors.forename: N R
authors.initials: NR
authors.lastname: Kitteringham
authors.forename: J B
authors.initials: JB
authors.lastname: Clarke
authors.forename: B K
authors.initials: BK
authors.lastname: Park
mesh_terms: D000655:Amodiaquine / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D001646:Bile / Q000378:metabolism*; D001711:Biotransformation; D002250:Carbon Radioisotopes; D003545:Cysteine / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007097:Imines / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D002250:Carbon Radioisotopes; D007097:Imines; D000655:Amodiaquine; D005978:Glutathione; D003545:Cysteine; D007654:Ketoconazole