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LPS binding protein does not participate in the pharmacokinetics of E5564

Tsukuba Research Laboratories, Eisai Co. Ltd, Ibaraki, Japan

Rika Ueda

Tsukuba Research Laboratories, Eisai Co. Ltd, Ibaraki, Japan

Tsutomu Kawata

Tsukuba Research Laboratories, Eisai Co. Ltd, Ibaraki, Japan

Sally Ishizaka

Tsukuba Research Laboratories, Eisai Co. Ltd, Ibaraki, Japan

Tsutomu Yoshimura

Tsukuba Research Laboratories, Eisai Co. Ltd, Ibaraki, Japan

E5564, a lipid A analogue, is a potent antagonist of lipopolysaccharide (LPS). Clinically, E5564 was developed as a possible therapy for treatment of sepsis and septic shock. Surface plasmon resonance (SPR) analysis indicates that E5564 binds to LPS binding protein (LBP), in a manner similar to LPS. Gel-filtration radioactive chromatograms of [¹⁴C]-E5564 in plasma revealed that E5564 initially distributes to the lipoprotein fractions, separated from high-density lipoprotein (HDL); the bound fraction is then released and binds to HDL. Similar results were obtained by heparin-manganese precipitation. At doses of E5564 relevant to its clinical use (i.e. 6 µg/ml), antibodies against LBP did not influence either the distribution of E5564 to non-HDL lipoprotein fractions or the transfer of E5564 from non-HDLs to HDL. Under these conditions, transfer of E5564 to HDL occurs similarly in the plasma of LBP knockout (KO) mice as in the plasma from wild-type mice. In addition, plasma clearance of E5564 in LBP KO mice is similar to that of wild-type mice. Thus, LBP binds E5564 in a manner similar to LPS, but does not play a role in E5564 redistribution/binding to lipoprotein and plasma clearance.

Key Words: Lipopolysaccharide • lipopolysaccharide binding protein • pharmacokinetics • E5564 • lipid A analogue

Journal of Endotoxin Research, Vol. 10, No. 3, 185-194 (2004)
DOI: 10.1177/09680519040100030501


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