The adverse reactions associated with the antimalarial amodiaquine (AQ), agranulocytosis and hepatotoxicity, have been attributed to the bioactivation of the drug to a quinone imine metabolite. Therefore the effect of chemical modification on the metabolism of AQ was studied, with particular reference to the prevention of bioactivation and the introduction of glucuronidation. Glutathione conjugates of AQ and desethylAQ were eliminated in bile after intraportal administration of [3H]AQ (54 mumol/kg, 20 microCi/kg) to anesthetized male CD1 mice. Thioether conjugates excreted into bile over 3 h accounted for 28% of the administered dose. Fluorine substitution at the C-4 position of AQ blocked bioactivation, as measured by formation of thioether conjugates, and resulted in a 5-fold decrease in biliary excretion of radiolabeled dose: ca 6% versus ca 29%. Additional substitution of a primary alcohol function into one of the ethyl moieties introduced glucuronidation as a pathway of elimination, with 10% of the dose being excreted in bile as an O-glucuronide of the parent compound over a 3-h period; excretion of total radioactivity in bile increased 2.5-fold. These substitutions resulted in a 2-fold greater excretion of radiolabel into urine: 41% and 39% for DFAQ and HDFAQ, respectively, versus 23% for AQ. Novel carboxylic acid and N-oxide metabolites of the fluorinated analogues were identified. AQ and the two fluorinated analogues had similar activity against Plasmodium berghei in mice. These results demonstrate that the metabolism of AQ can be diverted from extensive bioactivation to direct detoxication by simple chemical substitutions that do not impair pharmacological activity.