Original Paper

European Journal of Drug Metabolism and Pharmacokinetics

, Volume 37, Issue 1, pp 17-22

Ketotifen is an antimalarial prodrug of norketotifen with blood schizonticidal and liver-stage efficacy

  • Erin MilnerAffiliated withDivision of Experimental Therapeutics, Walter Reed Army Institute of Research Email author 
  • , Jason SousaAffiliated withDivision of Experimental Therapeutics, Walter Reed Army Institute of Research
  • , Brandon PybusAffiliated withDivision of Experimental Therapeutics, Walter Reed Army Institute of Research
  • , Jennifer AuschwitzAffiliated withDivision of Experimental Therapeutics, Walter Reed Army Institute of Research
  • , Diana CaridhaAffiliated withDivision of Experimental Therapeutics, Walter Reed Army Institute of Research
  • , Sean GardnerAffiliated withDivision of Experimental Therapeutics, Walter Reed Army Institute of Research
  • , Kristina GrauerAffiliated withDivision of Experimental Therapeutics, Walter Reed Army Institute of Research
  • , Erin HarrisAffiliated withDivision of Experimental Therapeutics, Walter Reed Army Institute of Research
  • , Mark HickmanAffiliated withDivision of Experimental Therapeutics, Walter Reed Army Institute of Research
    • , Michael P. KozarAffiliated withDivision of Experimental Therapeutics, Walter Reed Army Institute of Research
    • , Patricia LeeAffiliated withDivision of Experimental Therapeutics, Walter Reed Army Institute of Research
    • , Susan LeedAffiliated withDivision of Experimental Therapeutics, Walter Reed Army Institute of Research
    • , Qigui LiAffiliated withDivision of Experimental Therapeutics, Walter Reed Army Institute of Research
    • , Victor MelendezAffiliated withDivision of Experimental Therapeutics, Walter Reed Army Institute of Research
    • , Jay MoonAffiliated withDivision of Experimental Therapeutics, Walter Reed Army Institute of Research
    • , Franklyn NgundamAffiliated withDivision of Experimental Therapeutics, Walter Reed Army Institute of Research
    • , Michael O’NeilAffiliated withDivision of Experimental Therapeutics, Walter Reed Army Institute of Research
    • , Sandi ParriottAffiliated withDivision of Experimental Therapeutics, Walter Reed Army Institute of Research
    • , Brittney PotterAffiliated withDivision of Experimental Therapeutics, Walter Reed Army Institute of Research
    • , Rick SciottiAffiliated withDivision of Experimental Therapeutics, Walter Reed Army Institute of Research
    • , Anchalee TangteungAffiliated withDepartment of Veterinary Medicine, United States Army Medical Component, Armed Forces Research Institute of Medical Sciences
    • , Geoffrey S. DowAffiliated withDivision of Experimental Therapeutics, Walter Reed Army Institute of Research

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Abstract

Ketotifen is known to exhibit antimalarial activity in mouse and monkey malaria models. However, the low plasma levels and short half life of the drug do not adequately explain its in vivo efficacy. We synthesized most of the known metabolites of ketotifen and evaluated their antimalarial activity and pharmacokinetics in mice. Norketotifen, the de-methylated metabolite of ketotifen, was a more potent antimalarial in vitro as compared to ketotifen, and exhibited equivalent activity in vivo against asexual blood and developing liver-stage parasites. After ketotifen dosing, norketotifen levels were much higher than ketotifen relative to the IC50s of the compounds against Plasmodium falciparum in vitro. The data support the notion that the antimalarial activity of ketotifen in mice is mediated through norketotifen.

Keywords

Malaria drug development Ketotifen Blood-stage malaria Liver-stage malaria