title: Differential cytochrome P450 2D metabolism alters tafenoquine pharmacokinetics.
abstract: 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.
authors: Military Malaria Research Program, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors: Chau
authors: C
authors: Vuong
authors: Military Malaria Research Program, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors: Lisa H
authors: LH
authors: Xie
authors: Military Malaria Research Program, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors: Brittney M J
authors: BM
authors: Potter
authors: Military Malaria Research Program, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors: Jing
authors: J
authors: Zhang
authors: Military Malaria Research Program, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors: Ping
authors: P
authors: Zhang
authors: Military Malaria Research Program, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors: Dehui
authors: D
authors: Duan
authors: Military Malaria Research Program, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors: Christina K
authors: CK
authors: Nolan
authors: Military Malaria Research Program, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors: Richard J
authors: RJ
authors: Sciotti
authors: Military Malaria Research Program, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors: Victor E
authors: VE
authors: Zottig
authors: National Center for Natural Products Research, University of Mississippi, Oxford, Mississippi, USA.
authors: N P Dhammika
authors: NP
authors: Nanayakkara
authors: National Center for Natural Products Research, University of Mississippi, Oxford, Mississippi, USA Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, Mississippi, USA.
authors: Babu L
authors: BL
authors: Tekwani
authors: National Center for Natural Products Research, University of Mississippi, Oxford, Mississippi, USA Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, Mississippi, USA.
authors: Larry A
authors: LA
authors: Walker
authors: Military Malaria Research Program, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors: Philip L
authors: PL
authors: Smith
authors: Military Malaria Research Program, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors: Robert M
authors: RM
authors: Paris
authors: Military Malaria Research Program, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors: Lisa T
authors: LT
authors: Read
authors: Military Malaria Research Program, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors: Qigui
authors: Q
authors: Li
authors: Military Malaria Research Program, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors: Brandon S
authors: BS
authors: Pybus
authors: Military Malaria Research Program, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors: Jason C
authors: JC
authors: Sousa
authors: Military Malaria Research Program, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors: Gregory A
authors: GA
authors: Reichard
authors: United States Army Medical Material Development Activity, Frederick, Maryland, USA.
authors: Bryan
authors: B
authors: Smith
authors: Military Malaria Research Program, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA sean.r.marcsisin.mil@mail.mil.
authors: Sean R
authors: http://orcid.org/0000-0002-1988-6185
authors: SR
authors: Marcsisin
mesh_terms: D000634:Aminoquinolines / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D000962:Antimalarials / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001711:Biotransformation; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D006207:Half-Life; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011319:Primaquine / Q000493:pharmacokinetics
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; C055852:tafenoquine; D019389:Cytochrome P-450 CYP2D6; D011319:Primaquine