However, it seems difficult to harmonize these findings with the well-demonstrated enhancement of PQ anti-malarial efficacy by QN and CQ and the recent observations suggesting that CYP2D6 activity is essential to the anti-malarial efficacy of PQ [17, 29]. Overall, it raises the question of other mechanisms of action for these drugs, and perhaps important roles of other PQ metabolites that are not CYP2D6-dependent. For example, CQ and QN may affect transport processes for cellular uptake or extrusion of PQ or metabolites in a manner that could affect the overall efficacy or toxicity of PQ. Or the pathway to hydroxylated PQ products from other CYPs could be favoured, yielding active metabolites not seen in the absence of CQ or QN. In addition, the abundance of deaminated products in the presence of CQ/QN might be shunted into pathways that yield active metabolites with reduced toxicity. All of these possibilities must await further study, and especially the study in the clinic, where the interaction of PQ with QN and CQ can be assessed in terms of new knowledge of PQ metabolites and new methods for quantitating these.