Abstract
Primaquine (PQ) is an essential antimalarial drug but despite being developed over 70 years ago, its mode of action is unclear. Here, we demonstrate that hydroxylated-PQ metabolites (OH-PQm) are responsible for efficacy against liver and sexual transmission stages of Plasmodium falciparum. The antimalarial activity of PQ against liver stages depends on host CYP2D6 status, whilst OH-PQm display direct, CYP2D6-independent, activity. PQ requires hepatic metabolism to exert activity against gametocyte stages. OH-PQm exert modest antimalarial efficacy against parasite gametocytes; however, potency is enhanced ca.1000 fold in the presence of cytochrome P450 NADPH:oxidoreductase (CPR) from the liver and bone marrow. Enhancement of OH-PQm efficacy is due to the direct reduction of quinoneimine metabolites by CPR with the concomitant and excessive generation of H2O2, leading to parasite killing. This detailed understanding of the mechanism paves the way to rationally re-designed 8-aminoquinolines with improved pharmacological profiles.
Highlights
Primaquine (PQ) is an essential antimalarial drug but despite being developed over 70 years ago, its mode of action is unclear
YEM is a low metaboliser based on genotype analysis, it has a variation in the CYP2D6 allele (*4/*4); this was confirmed by incubation with the CYP2D6 probe debrisoquine[13] and measuring the metabolite 4-hydroxidebrisoquine by mass spectrometry (MS) (Supplementary Fig. 1), confirming that the NON hepatocyte lot had twofold higher CYP2D6 activity than the YEM lot
It is interesting to note that all OH-PQm show similar potency against liver stages, comparable to that seen for PQ in the presence of extensive metaboliser hepatocytes
Summary
Primaquine (PQ) is an essential antimalarial drug but despite being developed over 70 years ago, its mode of action is unclear. When gametocytes were treated with OH-PQm, we observed little to moderate gametocytocidal activity, with only demethoxylated species, 5,6-DPQ and 6OHPQQI, able to reduce gametocyte viability to less than 50 % of solvent control (Fig. 1g, (−)HLM).
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