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Novel Metabolites of Amodiaquine Formed by CYP1A1 and CYP1B1: Structure Elucidation Using Electrochemistry, Mass Spectrometry, and NMR

Discovery DMPK and Bioanalytical Chemistry (T.J.), Lead Generation (U.J.), Medicinal Chemistry (G.G.), Clinical Pharmacology and Drug Metabolism and Pharmacokinetics (L.W.), AstraZeneca R&D, Mölndal, Sweden; Department of Chemistry, Medicinal Chemistry, University of Gothenburg, Göteborg, Sweden (T.J.); and Department of Drug Metabolism and Pharmacokinetics/PD and Toxicology, African Institute of Biomedical Science and Technology, Harare, Zimbabwe (C.M.)

An aldehyde metabolite of amodiaquine and desethylamodiaquine has been identified. The aldehyde was the major metabolite formed in incubations with two recombinantly expressed human cytochromes P450 (rP450s), namely, CYP1A1 and CYP1B1. The aldehyde metabolite was also formed, to a lesser extent, in both human and rat liver microsomes. When comparing results from incubations with liver microsomes from 3-methylcholanthrene-treated rats (inducing CYP1A1 and CYP1B1) with those from noninduced rats, a 6-fold increase of the aldehyde metabolite was observed in the rat liver microsomes after 3-methylcholanthrene treatment. The metabolic oxidation was mimicked by the electrochemical system, and the electrochemical oxidation product was matched with the metabolite from the in vitro incubations. The electrochemical generation of the aldehyde metabolite was repeated on a preparative scale, and the proposed structure was confirmed by NMR. Trapping of the aldehyde metabolite was done with methoxyl amine. Trapping experiments with N-acetyl cysteine revealed that the aldehyde was further oxidized to an aldehyde quinoneimine species, both in the rP450 incubations and in the electrochemical system. Three additional new metabolites of amodiaquine and desethylamodiaquine were formed via rCYP1A1 and rCYP1B1. Trace amounts of these metabolites were also observed in incubations with liver microsomes from 3-methylcholanthrene-treated rats. Tentative structures of the metabolites and adducts were assigned based on liquid chromatography/tandem mass spectrometry in combination with accurate mass measurements.