The pharmacokinetics of DS-96, an N-alkylhomospermine analog designed to sequester bacterial lipopolysaccharides, has been determined in rodent species. The elimination half-life in mice and rats are about 400 and 500 min, respectively, with other PK parameters being quite similar in the two rodent species. Interestingly, the mouse intravenous plasma concentration time curves exhibit an apparent absorption phase. While the rat intravenous data did not exhibit a pronounced apparent absorption phase immediately following injection, plasma levels did increase between 10 and 30 min following an expected drop from time 0 to 5 min. The data are consistent with first-pass uptake, possibly by the lung, with back diffusion as a function of time. The observed C max values of 1.36 μg/mL in the mouse intraperitoneal model suggest that a plasma concentration of 0.5-1 μg/mL corresponds to complete protection for a 200 ng/animal dose of intraperitoneally administered LPS in the D-galactosamine-primed model of endotoxin-induced lethality.
Bibliographical noteFunding Information:
This work was supported from NIH grant 1R01 AI50107, the Kansas Technology Enterprise Corporation through the Centers of Excellence Program, and support from the Office of Therapeutics and Drug Discovery, University of Kansas.
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