Antimalarial 4‐aminoquinolines: mode of action and pharmacokinetics

Abstract

In the last ten years, the widespread increase in Plasmodium falciparum resistance to chloroquine has prompted research into antimalarial 4-aminoquinolines, empirically used up to now. The mechanism of action of 4-aminoquinolines is characterized by the concentration of the drug in the digestive vacuole of the intraerythrocytic parasite. Various hypotheses have been advanced to explain the specificity of action on the parasite; the most recent one is the inhibition of the haem polymerase 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 shown that chloroquine resistance can be reversed by various tricyclic drugs, which are able to restore the effective concentrations of chloroquine in the infected erythrocyte, but intrinsic mechanisms of action of these reversing agents are unknown. Four-aminoquinolines are extensively distributed in tissues and characterized by a long elimination half-life. Despite similarities in their chemical structures, these drugs show differences in their biotransformation and routes of elimination: chloroquine is partly metabolized into a monodesethylderivative and eliminated mainly by the kidney. In contrast, amodiaquine is a prodrug and amopyroquine is poorly metabolized; both drugs are excreted mainly in the bile. The understanding of the pharmacokinetics of 4-aminoquinolines has led to an improvement in empirically defined therapeutic regimens. Finally, the emergence of severe adverse-effects after prolonged prophylaxis with amodiaquine and the lack of cross resistance of Plasmodium falciparum between chloroquine and amopyroquine, have led to a proposal for the use of intramuscular amopyroquine as an alternative for the treatment of chloroquine-resistant malaria.

Effect of Concomitant Artesunate Administration and Cytochrome P4502C8 Polymorphisms on the Pharmacokinetics of Amodiaquine in Ghanaian Children with Uncomplicated Malaria

“…The data showed wide interindividual variation in the pharmacokinetic parameters of AQ, which is consistent with previous reports on AQ metabolism (25,30). In this study, however, the wide interindividual variation in AQ pharmacokinetics could reflect the maturational and physiological heterogeneity of this childhood population, which spanned most of the childhood age groups, each of which may be associated with distinct developmental and possibly distinct drug-metabolizing characteristics.…”

“…This effect of AS on AQ is likely to be an indirect effect of AS on disease, possibly through accelerated parasite clearance and rapid clinical recovery, with an indirect effect on the volume of distribution, or on clearance. This effect of AS on AQ could also result from drug-drug interaction, possibly through competition for protein binding sites between AQ and AS, since AQ and AS are both highly protein bound (25). The possibility of drug-drug interaction between AQ and AS, or between the metabolites of these two antimalarials, may have implications for the safety of the combination, especially in the context of coadministration of this regimen with other drugs, such as an antiretroviral drug, as has recently been reported (12).…”

Development, Evaluation, and Application of an In Silico Model for Antimalarial Drug Treatment and Failure

“…The model predicted a PoC of 32 days for LF, which is very close to the reported range in fully sensitive parasites of 24 to 30 days (56, 58), although we do note that PoC is reduced as resistance spreads (26). The PoC for CQ was longer than expected, at 52 days, but this may be due to the long terminal elimination half-life values reported for CQ (21,47), which may not properly reflect elimination rates at higher, physiologically active concentrations (16). Since MQ and PQ are not yet regularly deployed in areas of high transmission, we were unable to find published estimates of PoC for either drug, but we did find papers comparing reinfection rates between two different drug regimens used in the same setting.…”

Population Pharmacokinetic and Pharmacodynamic Modeling of Amodiaquine and Desethylamodiaquine in Women with Plasmodium vivax Malaria during and after Pregnancy

“…Amodiaquine and desethylamodiaquine are extensively bound (90 to 95%) to plasma proteins (43). Desethylamodiaquine, but not amodiaquine, is accumulated in erythrocytes, with an erythrocyte-to-plasma ratio of 3:1 in healthy subjects.…”