Milner Erin, Sousa Jason, Pybus Brandon, Melendez Victor, Gardner Sean, Grauer Kristina, Moon Jay, Carroll Dustin, Auschwitz Jennifer, Gettayacamin Montip, Lee Patricia, Leed Susan, McCalmont William, Norval Suzanne, Tungtaeng Anchalee, Zeng Qiang, Kozar Michael, Read Kevin D, Li Qigui, Dow Geoffrey
Department of Medicinal Chemistry, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD 20910-7500, USA,
Eur J Drug Metab Pharmacokinet. 2011 Sep;36(3):151-8. doi: 10.1007/s13318-011-0047-8. Epub 2011 Jul 13.
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.
WR319691在体外已显示出对恶性疟原虫有合理的效力，并且在MDCK细胞单层中的通透性降低，作为我们筛选流程的一部分，这导致了进一步的体内分析。在小鼠静脉注射5mg/kg剂量后评估了单剂量药代动力学。WR319691的最大结合和未结合脑内水平分别为97和0.05ng/g，而甲氟喹约为1600和3.2ng/g。WR319691在血浆中的半衰期约为13小时，而甲氟喹为23小时。还评估了几种N-脱烷基代谢物的药代动力学。在静脉注射5mg/kg WR319691后，检测到了六种代谢物中的五种，与相同剂量的甲氟喹相比，最大总脑内水平和游离脑内水平均较低。这些数据提供了概念验证，即在不显著降低体外对恶性疟原虫效力的情况下，在体内大幅降低4-位修饰喹啉甲醇的脑内水平是可行的。
