Abstract
BackgroundThe activity and haemolytic toxicity associated with primaquine has been linked to its reactive metabolites. The reactive metabolites are thought to be primarily formed through the action of cytochrome P450-mediated pathways. Human erythrocytes generally are not considered a significant contributor to drug biotransformation. As erythrocytes are the target of primaquine toxicity, the ability of erythrocytes to mediate the formation of reactive oxidative primaquine metabolites in the absence of hepatic enzymes, was evaluated.MethodsPrimaquine and its enantiomers were incubated separately with human red blood cells and haemoglobin. Post-incubation analysis was performed with UPLC–MS/MS to identify products of biotransformation.ResultsThe major metabolite detected was identified as primaquine-5,6-orthoquinone, reflecting the pathway yielding putative active and haematotoxic metabolites of primaquine, which was formed by oxidative demethylation of 5-hydroxyprimaquine. Incubation of primaquine with haemoglobin in a cell-free system yielded similar results. It appears that the observed biotransformation is due to non-enzymatic processes, perhaps due to reactive oxygen species (ROS) present in erythrocytes or in the haemoglobin incubates.ConclusionThis study presents new evidence that primaquine-5,6-orthoquinone, the metabolite of primaquine reflecting the oxidative biotransformation pathway, is generated in erythrocytes, probably by non-enzymatic means, and may not require transport from the liver or other tissues.
Highlights
The activity and haemolytic toxicity associated with primaquine has been linked to its reactive metab‐ olites
A substantial amount of PQ-orthoquinone was detected in the red blood cells (RBC) incubates of racemic PQ and the individual enantiomers, with a rapid disappearance of PQ within the first hour
In the erythrocyte incubations, the majority of the PQ is rapidly partitioned into the red cell fraction, with much reduced concentrations in the medium
Summary
The activity and haemolytic toxicity associated with primaquine has been linked to its reactive metab‐ olites. The association of primaquine (PQ) with haemolytic toxicity in certain individuals has been recognized since the introduction of the anti-malarial drug over six decades [1] This toxicity was subsequently determined to be associated with a genetic deficiency in glucose-6-phosphate dehydrogenase (G6PD) [2]. PQ is used for the radical cure of the persistent liver stages of Plasmodium vivax and Plasmodium ovale responsible for relapsing malaria [3,4,5], as well as a prophylactic for all forms of human malaria and as a gametocytocide for transmission interruption in falciparum malaria [6,7,8] Despite this long history of clinical use, the mechanisms of biotransformation, efficacy and haemotoxicity are still not fully understood [3,4,5].
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