title: The metabolism of primaquine to its active metabolite is dependent on CYP 2D6.
abstract: BACKGROUND
  The efficacy of the 8-aminoquinoline (8AQ) drug primaquine (PQ) has been historically linked to CYP-mediated metabolism. Although to date no clear evidence exists in the literature that unambiguously assigns the metabolic pathway or specific metabolites necessary for activity, recent literature suggests a role for CYP 2D6 in the generation of redox active metabolites.
  
  
  METHODS
  In the present study, the specific CYP 2D6 inhibitor paroxetine was used to assess its effects on the production of specific phenolic metabolites thought to be involved in PQ efficacy. Further, PQ causal prophylactic (developing liver stage) efficacy against Plasmodium berghei in CYP 2D knockout mice was assessed in comparison with a normal C57 background and with humanized CYP 2D6 mice to determine the direct effects of CYP 2D6 metabolism on PQ activity.
  
  
  RESULTS
  PQ exhibited no activity at 20 or 40 mg/kg in CYP 2D knockout mice, compared to 5/5 cures in normal mice at 20 mg/kg. The activity against developing liver stages was partially restored in humanized CYP 2D6 mice.
  
  
  CONCLUSIONS
  These results unambiguously demonstrate that metabolism of PQ by CYP 2D6 is essential for anti-malarial causal prophylaxis efficacy.
authors.forename: Brandon S
authors.initials: BS
authors.lastname: Pybus
authors.forename: Sean R
authors.initials: SR
authors.lastname: Marcsisin
authors.forename: Xiannu
authors.initials: X
authors.lastname: Jin
authors.forename: Gregory
authors.initials: G
authors.lastname: Deye
authors.forename: Jason C
authors.initials: JC
authors.lastname: Sousa
authors.forename: Qigui
authors.initials: Q
authors.lastname: Li
authors.forename: Diana
authors.initials: D
authors.lastname: Caridha
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zeng
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Reichard
authors.forename: Christian
authors.initials: C
authors.lastname: Ockenhouse
authors.forename: Jason
authors.initials: J
authors.lastname: Bennett
authors.forename: Larry A
authors.initials: LA
authors.lastname: Walker
authors.forename: Colin
authors.initials: C
authors.lastname: Ohrt
authors.forename: Victor
authors.initials: V
authors.lastname: Melendez
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism*; D006900:Hydroxylation; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010962:Plasmodium berghei; D011319:Primaquine / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000962:Antimalarials; D019389:Cytochrome P-450 CYP2D6; D011319:Primaquine