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.
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This manuscript was reviewed by the Walter Reed Army Institute of Research and the US Army Medical Research and Materiel Command, and there is no objection to its publication or dissemination. The opinions expressed herein are those of the authors and do not necessarily reflect the views or opinions of the Department of the Army and the Department of Defense. All animal experiments were conducted in compliance with the Animal Welfare Act and other federal statutes and regulations relating to animals and experiments involving animals and adhere to the principles stated in the Guide for the Care and Use of Laboratory Animals (National Academy Press, 1996).
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Milner, E., Sousa, J., Pybus, B. et al. Ketotifen is an antimalarial prodrug of norketotifen with blood schizonticidal and liver-stage efficacy. Eur J Drug Metab Pharmacokinet 37, 17–22 (2012). https://doi.org/10.1007/s13318-012-0080-2
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DOI: https://doi.org/10.1007/s13318-012-0080-2