title: Cytochrome P450 2D-mediated metabolism is not necessary for tafenoquine and primaquine to eradicate the erythrocytic stages of Plasmodium berghei.
abstract: BACKGROUND
  Due to the ability of the 8-aminoquinolines (8AQs) to kill different stages of the malaria parasite, primaquine (PQ) and tafenoquine (TQ) are vital for causal prophylaxis and the eradication of erythrocytic Plasmodium sp. parasites. Recognizing the potential role of cytochrome (CYP) 450 2D6 in the metabolism and subsequent hepatic efficacy of 8-aminoquinolines, studies were designed to explore whether CYP2D-mediated metabolism was related to the ability of single-dose PQ and TQ to eliminate the asexual and sexual erythrocytic stages of Plasmodium berghei.
  
  
  METHODS
  An IV P. berghei sporozoite murine challenge model was utilized to directly compare causal prophylactic and erythrocytic activity (asexual and sexual parasite stages) dose-response relationships in C57BL/6 wild-type (WT) mice and subsequently compare the erythrocytic activity of PQ and TQ in WT and CYP2D knock-out (KO) mice.
  
  
  RESULTS
  Single-dose administration of either 25 mg/kg TQ or 40 mg/kg PQ eradicated the erythrocytic stages (asexual and sexual) of P. berghei in C57BL WT and CYP2D KO mice. In WT animals, the apparent elimination of hepatic infections occurs at lower doses of PQ than are required to eliminate erythrocytic infections. In contrast, the minimally effective dose of TQ needed to achieve causal prophylaxis and to eradicate erythrocytic parasites was analogous.
  
  
  CONCLUSIONS
  The genetic deletion of the CYP2D cluster does not affect the ability of PQ or TQ to eradicate the blood stages (asexual and sexual) of P. berghei after single-dose administration.
authors.affiliation: Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD, USA. erin.milner@us.army.mil.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Milner
authors.affiliation: Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Berman
authors.affiliation: Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Caridha
authors.affiliation: United States Army Medical Materiel Development Authority (USAMMDA), Ft Detrick, Frederick, MD, USA.
authors.forename: Samuel P
authors.initials: SP
authors.lastname: Dickson
authors.affiliation: Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Hickman
authors.affiliation: Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD, USA.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Lee
authors.affiliation: Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD, USA.
authors.forename: Sean R
authors.initials: SR
authors.lastname: Marcsisin
authors.affiliation: United States Army Medical Materiel Development Authority (USAMMDA), Ft Detrick, Frederick, MD, USA.
authors.forename: Lisa T
authors.initials: LT
authors.lastname: Read
authors.affiliation: Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD, USA.
authors.forename: Norma
authors.initials: N
authors.lastname: Roncal
authors.affiliation: Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Vesely
authors.affiliation: Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD, USA.
authors.forename: Lisa H
authors.initials: LH
authors.lastname: Xie
authors.affiliation: Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD, USA.
authors.forename: Qigui
authors.initials: Q
authors.lastname: Li
mesh_terms: D000634:Aminoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000494:pharmacology*; D018890:Chemoprevention / Q000379:methods; D019389:Cytochrome P-450 CYP2D6 / Q000172:deficiency / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004358:Drug Therapy / Q000379:methods; D005260:Female; D008288:Malaria / Q000188:drug therapy*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010962:Plasmodium berghei / Q000187:drug effects*; D011319:Primaquine / Q000008:administration & dosage / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; C055852:tafenoquine; D019389:Cytochrome P-450 CYP2D6; D011319:Primaquine