title: Pre-clinical evaluation of CYP 2D6 dependent drug-drug interactions between primaquine and SSRI/SNRI antidepressants.
abstract: The liver-stage anti-malarial activity of primaquine and other 8-aminoquinoline molecules has been linked to bio-activation through CYP 2D6 metabolism. Factors such as CYP 2D6 poor metabolizer status and/or co-administration of drugs that inhibit/interact with CYP 2D6 could alter the pharmacological properties of primaquine.
  
  
  
  In the present study, the inhibitory potential of the selective serotonin reuptake inhibitor (SSRI) and serotonin norepinephrine reuptake inhibitor (SNRI) classes of antidepressants for CYP 2D6-mediated primaquine metabolism was assessed using in vitro drug metabolism and in vivo pharmacological assays.
  
  
  
  The SSRI/SNRI classes of drug displayed a range of inhibitory activities on CYP 2D6-mediated metabolism of primaquine in vitro (IC50 1-94 μM). Fluoxetine and paroxetine were the most potent inhibitors (IC50 ~1 µM) of CYP 2D6-mediated primaquine metabolism, while desvenlafaxine was the least potent (IC50 ~94 µM). The most potent CYP 2D6 inhibitor, fluoxetine, was chosen to investigate the potential pharmacological consequences of co-administration with primaquine in vivo. The pharmacokinetics of a CYP 2D6-dependent primaquine metabolite were altered upon co-administration with fluoxetine. Additionally, in a mouse malaria model, co-administration of fluoxetine with primaquine reduced primaquine anti-malarial efficacy.
  
  
  
  These results are the first from controlled pre-clinical experiments that indicate that primaquine pharmacological properties can be modulated upon co-incubation/administration with drugs that are known to interact with CYP 2D6. These results highlight the potential for CYP 2D6-mediated drug-drug interactions with primaquine and indicate that the SSRI/SNRI antidepressants could be used as probe molecules to address the primaquine-CYP 2D6 DDI link in clinical studies. Additionally, CYP 2D6-mediated drug-drug interactions can be considered when examining the possible causes of human primaquine therapy failures.
authors.affiliation: Military Malaria Research Program, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, 20910, USA.
authors.forename: Xiannu
authors.initials: X
authors.lastname: Jin
authors.affiliation: Military Malaria Research Program, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, 20910, USA.
authors.forename: Brittney
authors.initials: B
authors.lastname: Potter
authors.affiliation: Military Malaria Research Program, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, 20910, USA.
authors.forename: Thu-Lan
authors.initials: TL
authors.lastname: Luong
authors.affiliation: Military Malaria Research Program, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, 20910, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Nelson
authors.affiliation: Military Malaria Research Program, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, 20910, USA.
authors.forename: Chau
authors.initials: C
authors.lastname: Vuong
authors.affiliation: Military Malaria Research Program, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, 20910, USA.
authors.forename: Corttney
authors.initials: C
authors.lastname: Potter
authors.affiliation: Military Malaria Research Program, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, 20910, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Xie
authors.affiliation: Military Malaria Research Program, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, 20910, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Military Malaria Research Program, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, 20910, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Military Malaria Research Program, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, 20910, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Sousa
authors.affiliation: Military Malaria Research Program, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, 20910, USA.
authors.forename: Qigui
authors.initials: Q
authors.lastname: Li
authors.affiliation: Military Malaria Research Program, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, 20910, USA.
authors.forename: Brandon S
authors.initials: BS
authors.lastname: Pybus
authors.affiliation: Military Malaria Research Program, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, 20910, USA.
authors.forename: Mara
authors.initials: M
authors.lastname: Kreishman-Deitrick
authors.affiliation: Military Malaria Research Program, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, 20910, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Hickman
authors.affiliation: Military Malaria Research Program, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, 20910, USA.
authors.forename: Philip L
authors.initials: PL
authors.lastname: Smith
authors.affiliation: Military Malaria Research Program, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, 20910, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Paris
authors.affiliation: Military Malaria Research Program, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, 20910, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Reichard
authors.affiliation: Military Malaria Research Program, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, 20910, USA. sean.r.marcsisin.mil@mail.mil.
authors.forename: Sean R
authors.initials: SR
authors.lastname: Marcsisin
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D000962:Antimalarials / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D004195:Disease Models, Animal; D004347:Drug Interactions; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008288:Malaria / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011319:Primaquine / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents; D000962:Antimalarials; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; D019389:Cytochrome P-450 CYP2D6; D011319:Primaquine
keywords: Antimalarial; CYP 2D6; Drug metabolism; Drug–drug interactions; Pharmacokinetics; Primaquine; Relapsing malaria