EFFECT OF DISPOSITION OF MANNICH ANTIMALARIAL AGENTS ON THEIR PHARMACOLOGY AND TOXICOLOGY

The use of the antimalarial agent amodiaquine has been curtailed due t o drug-induced idiosyncratic reactions. These have been attributed to the formation of a protein-reactive quinoneimine species via oxidation of the l-aminophenol group, Therefore, the effects of chemical modifi cations on the disposition of amodiaquine in relation to its metabolis m, distribution, and pharmacological activity have been investigated. The inclusion of a group at the C-5' position of amodiaquine reduced o r eliminated bioactivation, as determined by glutathione conjugate for mation in vivo. This can be seen in two series of C-5'-substituted com pounds: the bis-Mannich antimalarial agents, including cycloquine and pyronaridine, and mono-Mannich antimalarial agents containing a 5'-chl orophenyl group (tebuquine and 5'-CIPAQ). Chemical substitution at the C-5' position also resulted in compounds which underwent slower elimi nation (<5% of the dose excreted into bile and urine, compared with 50 % for amodiaquine) and increased levels of accumulation in tissue (10% of the dose in the liver at 48 h compared with 1% with amodiaquine). This may be due to an increase in either the lipophilicity or the basi city of the analogs and may reflect the lack of metabolic clearance fo r these compounds. The alteration in the disposition following the int roduction of the C-5' substituent resulted in an increased duration of antimalarial activity in the mouse compared with that for amodiaquine . While this is desirable in the treatment of malaria, repeated admini stration for prophylaxis may induce toxicity through accumulation. The refore, by simple chemical modification it is possible to block the bi oactivation of amodiaquine while maintaining and in some cases extendi ng the duration of antimalarial activity.