Cytochrome P450 (CYP) 2D metabolism is required for the liver-stage
antimalarial efficacy of the
8-aminoquinoline molecule
tafenoquine in mice. This could be problematic for Plasmodium vivax radical cure, as the human CYP 2D ortholog (2D6) is highly polymorphic. Diminished
CYP 2D6 enzyme activity, as in the poor-metabolizer phenotype, could compromise radical curative efficacy in humans. Despite the importance of CYP 2D metabolism for
tafenoquine liver-stage efficacy, the exact role that CYP 2D metabolism plays in the metabolism and pharmacokinetics of
tafenoquine and other
8-aminoquinoline molecules has not been extensively studied. In this study, a series of
tafenoquine pharmacokinetic experiments were conducted in mice with different CYP 2D metabolism statuses, including wild-type (WT) (reflecting extensive metabolizers for
CYP 2D6 substrates) and CYPmouse 2D knockout (KO) (reflecting poor metabolizers for
CYP 2D6 substrates) mice. Plasma and liver pharmacokinetic profiles from a single 20-mg/kg of
body weight dose of
tafenoquine differed between the strains; however, the differences were less striking than previous results obtained for
primaquine in the same model. Additionally, the presence of a 5,6-ortho-quinone
tafenoquine metabolite was examined in both mouse strains. The 5,6-ortho-quinone species of
tafenoquine was observed, and concentrations of the metabolite were highest in the WT extensive-metabolizer phenotype. Altogether, this study indicates that CYP 2D metabolism in mice affects
tafenoquine pharmacokinetics and could have implications for human
tafenoquine pharmacokinetics in polymorphic
CYP 2D6 human populations.