title: Differential CYP 2D6 metabolism alters primaquine pharmacokinetics.
abstract: Primaquine (PQ) metabolism by the cytochrome P450 (CYP) 2D family of enzymes is required for antimalarial activity in both humans (2D6) and mice (2D). Human CYP 2D6 is highly polymorphic, and decreased CYP 2D6 enzyme activity has been linked to decreased PQ antimalarial activity. Despite the importance of CYP 2D metabolism in PQ efficacy, the exact role that these enzymes play in PQ metabolism and pharmacokinetics has not been extensively studied in vivo. In this study, a series of PQ pharmacokinetic experiments were conducted in mice with differential CYP 2D metabolism characteristics, including wild-type (WT), CYP 2D knockout (KO), and humanized CYP 2D6 (KO/knock-in [KO/KI]) mice. Plasma and liver pharmacokinetic profiles from a single PQ dose (20 mg/kg of body weight) differed significantly among the strains for PQ and carboxy-PQ. Additionally, due to the suspected role of phenolic metabolites in PQ efficacy, these were probed using reference standards. Levels of phenolic metabolites were highest in mice capable of metabolizing CYP 2D6 substrates (WT and KO/KI 2D6 mice). PQ phenolic metabolites were present in different quantities in the two strains, illustrating species-specific differences in PQ metabolism between the human and mouse enzymes. Taking the data together, this report furthers understanding of PQ pharmacokinetics in the context of differential CYP 2D metabolism and has important implications for PQ administration in humans with different levels of CYP 2D6 enzyme activity.
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: 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: 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: 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: Thu-Lan T
authors: TL
authors: Luong
authors: National Center for Natural Products Research, University of Mississippi, Mississippi, USA.
authors: H M T
authors: HM
authors: Bandara Herath
authors: National Center for Natural Products Research, University of Mississippi, Mississippi, USA.
authors: N P
authors: NP
authors: Dhammika Nanayakkara
authors: National Center for Natural Products Research, University of Mississippi, Mississippi, USA Department of Pharmacology, School of Pharmacy, University of Mississippi, Mississippi, USA.
authors: Babu L
authors: BL
authors: Tekwani
authors: National Center for Natural Products Research, University of Mississippi, Mississippi, USA Department of Pharmacology, School of Pharmacy, University of Mississippi, 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: 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: 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: 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: SR
authors: Marcsisin
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001711:Biotransformation; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011319:Primaquine / Q000493:pharmacokinetics*
chemical_list: D000962:Antimalarials; D019389:Cytochrome P-450 CYP2D6; D011319:Primaquine
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