ANTIMALARIAL 4-AMINOQUINOLINES - MODE OF ACTION AND PHARMACOKINETICS

In the last ten years, the widespread increase in Plasmodium falciparu m resistance to chloroquine has prompted research into antimalarial 4- aminoquinolines, empirically used up to now. The mechanism of action o f 4-aminoquinolines is characterized by the concentration of the drug in the digestive vacuole of the intraerythrocytic parasite. Various hy potheses have been advanced to explain the specificity of action on th e parasite; the most recent one is the inhibition of the haem polymera se of the parasite, leading to the accumulation of soluble haem toxic for the parasite. Chloroquine-resistant parasites accumulate the drug to a lesser extent than do sensitive parasites. Recent findings have s hown that chloroquine resistance can be reversed by various tricyclic drugs, which are able to restore the effective concentrations of chlor oquine in the infected erythrocyte, but intrinsic mechanisms of action of these reversing agents are unknown. Four-aminoquinolines are exten sively distributed in tissues and characterized by a long elimination half-life. Despite similarities in their chemical structures, these dr ugs show differences in their biotransformation and routes of eliminat ion: chloroquine is partly metabolized into a monodesethylderivative a nd eliminated mainly by the kidney. In contrast, amodiaquine is a prod rug and amopyroquine is poorly metabolized; both drugs are excreted ma inly in the bile. The understanding of the pharmacokinetics of 4-amino quinolines has led to an improvement in empirically defined therapeuti c regimens. Finally, the emergence of severe adverse-effects after pro longed prophylaxis with amodiaquine and the lack of cross resistance o f Plasmodium falciparum between chloroquine and amopyroquine, have led to a proposal for the use of intramuscular amopyroquine as an alterna tive for the treatment of chloroquine-resistant malaria.