Characterization of in vivo metabolites of WR319691, a novel compound with activity against Plasmodium falciparum

Erin Milner, Jason Sousa, Brandon Pybus, Victor Melendez, Sean Gardner, Kristina Grauer, Jay Moon, Dustin Carroll, Jennifer Auschwitz, Montip Gettayacamin, Patricia Lee, Susan Leed, William McCalmont, Suzanne Norval, Anchalee Tungtaeng, Qiang Zeng, Michael Kozar, Kevin D. Read, Qigui Li, Geoffrey Dow

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    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.

    Original languageEnglish
    Pages (from-to)151-158
    Number of pages8
    JournalEuropean Journal of Drug Metabolism and Pharmacokinetics
    Volume36
    Issue number3
    DOIs
    Publication statusPublished - 2011

    Cite this

    Milner, E., Sousa, J., Pybus, B., Melendez, V., Gardner, S., Grauer, K., Moon, J., Carroll, D., Auschwitz, J., Gettayacamin, M., Lee, P., Leed, S., McCalmont, W., Norval, S., Tungtaeng, A., Zeng, Q., Kozar, M., Read, K. D., Li, Q., & Dow, G. (2011). Characterization of in vivo metabolites of WR319691, a novel compound with activity against Plasmodium falciparum. European Journal of Drug Metabolism and Pharmacokinetics, 36(3), 151-158. https://doi.org/10.1007/s13318-011-0047-8