Abstract
WR319691 has been shown to exhibit reasonable Plasmodium falciparum potency in vitro and exhibits reduced permeability across MDCK cell monolayers, which as part of our screening cascade led to further in vivo analysis. Single-dose pharmacokinetics was evaluated after an IV dose of 5 mg/kg in mice. Maximum bound and unbound brain levels of WR319691 were 97 and 0.05 ng/g versus approximately 1,600 and 3.2 ng/g for mefloquine. The half-life of WR319691 in plasma was approximately 13 h versus 23 h for mefloquine. The pharmacokinetics of several N-dealkylated metabolites was also evaluated. Five of six of these metabolites were detected and maximum total and free brain levels were all lower after an IV dose of 5 mg/kg WR319691 compared to mefloquine at the same dose. These data provide proof of concept that it is feasible to substantially lower the brain levels of a 4-position modified quinoline methanol in vivo without substantially decreasing potency against P. falciparum in vitro.
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We gratefully acknowledge substantial financial support from Medicines for Malaria Venture, Military Infectious Diseases Research Program (MIDRP), and the United States Department of Defense.
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This manuscript was reviewed by the Walter Reed Army Institute of Research and the U.S. 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). The MDCK permeability assays were performed under contract by Absorption Systems (Exton PA).
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Milner, E., Sousa, J., Pybus, B. et al. Characterization of in vivo metabolites of WR319691, a novel compound with activity against Plasmodium falciparum . Eur J Drug Metab Pharmacokinet 36, 151–158 (2011). https://doi.org/10.1007/s13318-011-0047-8
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DOI: https://doi.org/10.1007/s13318-011-0047-8