For moderate CYP2D6 inhibitors like CQ and QN, substrate-specific or orientation/conformation-specific inhibition may be expected. This may explain varying degrees of inhibition on the individual CYP2D6 metabolites of PQ or the individual enantiomer substrates. However, such dramatic inhibition of the formation of the mono-hydroxylated primaquines as was observed at the early time points may have significant pharmacodynamic implications. This might favour alternative metabolic pathways leading to significant changes in therapeutic response, and may play major roles in the earlier observation of mitigated toxicity when PQ was combined with CQ and QN.