Disposition of amodiaquine and related antimalarial agents in human neutrophils: implications for drug design.
The development and clinical use of 4-aminoquinoline antimalarial agents such as amodiaquine have been limited by toxicity to neutrophils. We have investigated the chemical basis of amodiaquine-induced toxicity and compared the findings with those for established antimalarial drugs proposed for human use. Amodiaquine, like chloroquine, mefloquine and halofantrine, was lysosomotropic and accumulated in human neutrophils. Amodiaquine did not lead to impairment of either cellular function or cell viability at therapeutic levels. In contrast to other antimalarial agents, amodiaquine (because it contains a 4-aminophenol function) depleted glutathione in activated neutrophils, by formation of an electrophilic quinoneimine metabolite. Bioactivation was accompanied by the expression of a drug-related antigen on the cell surface, which was recognized by drug-specific antibodies, suggesting that a type II hypersensitivity reaction is responsible for the observed toxicity. Similar bioactivation and accumulation were observed for the structurally related amopyroquine. The effects of chemical modifications at the 3'- and 5'-positions, which are known to enhance antimalarial activity, were also investigated. The introduction of a lipophilic 5'-chlorophenyl group and 3'-t-butyl group blocked bioactivation but enhanced cellular accumulation, with resultant impairment of function and neutrophil viability, whereas introduction of a second cationic dialkylamino group (bis-mannich compounds) blocked bioactivation and reduced cellular accumulation, without producing noticeable effects on cellular function and viability. These data provide a chemical rationale for the idiosyncratic agranulocytosis observed with amodiaquine, and they suggest that similar toxicity might be anticipated for amopyroquine but is less likely with bis-mannich antimalarial agents such as pyronaridine.
Naisbitt
D J
DJ
Department of Pharmacology and Therapeutics, The University of Liverpool, England.
Ruscoe
J E
JE
Williams
D
D
O'Neill
P M
PM
Pirmohamed
M
M
Park
B K
BK
D000655:Amodiaquine / Q000031:analogs & derivatives* / Q000097:blood* / Q000493:pharmacokinetics / Q000633:toxicity; D000962:Antimalarials / Q000097:blood* / Q000493:pharmacokinetics / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D005978:Glutathione / Q000097:blood; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015394:Molecular Structure; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014316:Tritium
D000962:Antimalarials; D014316:Tritium; D000655:Amodiaquine; D005978:Glutathione; D013755:Tetradecanoylphorbol Acetate