Methaemoglobinaemia and G6PD deficiency
The discrepancy between 8-aminoquinoline haemolytic toxicity and methaemoglobinemia has been noted widely (26). In the research which led to registration of primaquine, Edgcomb et al (24) noted no correlation between haemolysis and methaemoglobinaemia following pamaquine or primaquine. The erythrocytes in G6PD deficiency have a reduced ability to reduce methaemoglobin in the presence of “electron-donors”, such as the bioactive metabolites of primaquine or methylene blue (this is the basis of the methylene blue methaemoglobin reduction test developed to diagnose G6PD deficiency). This is because of the reduced intraerythrocytic activity of the NADPH dependent methemoglobin reductase. Brewer et al showed that whereas G6PD deficient individuals had increased levels of methaemoglobinaemia following oral sodium nitrite (an oxidizing agent which does not cause haemolysis), they haddecreased levels of methaemoglobinemia following primaquine (26) (Figure 7). This apparent paradox was explained by the iatrogenic haemolysis of the older erythrocytes which contained the highest concentrations of methaemoglobin. Other mechanisms are also possible, such as the sequestration of the primaquine oxidant metabolites in the oxidized haemoglobin Heinz bodies. The mechanism of 8-aminoquinoline haemolytic toxicity has not been explained satisfactorily but clearly involves more than broad oxidant stress.