Metabolism of a candidate 8-aminoquinoline antimalarial agent, WR 238605, by rat liver microsomes

The in vitro metabolism of the 8-aminoquinoline, 8-(4-amino-1- methylbutylamino-2,6-dimethoxy-4-methyl-5-(3-trifluromethyl- phenoxy)quinoline (WR 238605), by rat liver microsomes was studied. After incubation of WR 238605 with rat liver microsomes, the metabolites were isolated either by direct solvent extraction or by extraction in the presence of ethyl chloroformate. WR 238605 was extensively metabolized to aminophenolic compounds, which underwent air oxidation during the isolation process to a mixture of quinones and quinoneimines. Because of the instability of the metabolites toward air oxidation, most of them could only be isolated as the ethoxycarbonyl derivatives by in situ derivatization with ethyl chloroformate. The metabolism of WR 238605 involved the expected metabolic pathways, such as O-demethylation, N-dealkylation, N-oxidation, and oxidative deamination. In addition, C-hydroxylation involving the 8-aminoalkylamino side chain, which was previously unknown for 8-aminoquinoline analogs, was found to be an important metabolic pathway for WR 238605. Most of the metabolites retained the 5-(m-trifluoromethyl)phenoxy group of WR 238605. Direct and indirect supporting evidence for the structure of the metabolites of WR 238605 came from the concomitant study of the in vitro metabolism of six other compounds that are putative metabolites of WR 238605.