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

  • Erin Milner
  • Jason Sousa
  • Brandon Pybus
  • Jennifer Auschwitz
  • Diana Caridha
  • Sean Gardner
  • Kristina Grauer
  • Erin Harris
  • Mark Hickman
  • Michael P. Kozar
  • Patricia Lee
  • Susan Leed
  • Qigui Li
  • Victor Melendez
  • Jay Moon
  • Franklyn Ngundam
  • Michael O’Neil
  • Sandi Parriott
  • Brittney Potter
  • Rick Sciotti
  • Anchalee Tangteung
  • Geoffrey S. Dow
Original Paper

DOI: 10.1007/s13318-012-0080-2

Cite this article as:
Milner, E., Sousa, J., Pybus, B. et al. Eur J Drug Metab Pharmacokinet (2012) 37: 17. doi:10.1007/s13318-012-0080-2

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 developmentKetotifenBlood-stage malariaLiver-stage malaria

Supplementary material

13318_2012_80_MOESM1_ESM.pdf (4.1 mb)
Supplementary material 1 (PDF 4151 kb)
13318_2012_80_MOESM2_ESM.pdf (3.6 mb)
Supplementary material 2 (PDF 3726 kb)

Copyright information

© Springer-Verlag France (outside the USA) 2012

Authors and Affiliations

  • Erin Milner
    • 1
  • Jason Sousa
    • 1
  • Brandon Pybus
    • 1
  • Jennifer Auschwitz
    • 1
  • Diana Caridha
    • 1
  • Sean Gardner
    • 1
  • Kristina Grauer
    • 1
  • Erin Harris
    • 1
  • Mark Hickman
    • 1
  • Michael P. Kozar
    • 1
  • Patricia Lee
    • 1
  • Susan Leed
    • 1
  • Qigui Li
    • 1
  • Victor Melendez
    • 1
  • Jay Moon
    • 1
  • Franklyn Ngundam
    • 1
  • Michael O’Neil
    • 1
  • Sandi Parriott
    • 1
  • Brittney Potter
    • 1
  • Rick Sciotti
    • 1
  • Anchalee Tangteung
    • 2
  • Geoffrey S. Dow
    • 1
  1. 1.Division of Experimental TherapeuticsWalter Reed Army Institute of ResearchSilver SpringUSA
  2. 2.Department of Veterinary MedicineUnited States Army Medical Component, Armed Forces Research Institute of Medical SciencesBangkokThailand