LPS binding protein does not participate in the pharmacokinetics of E5564

• Published in: Journal of endotoxin research Vol. 10; no. 3; pp. 185 - 194
• Main Authors: Kaneko, Kazuhiro, Ueda, Rika, Kawata, Tsutomu, Ishizaka, Sally, Yoshimura, Tsutomu
• Format: Journal Article
• Language: English
• Published: London, England Sage Publications 01.06.2004
• Subjects: Acute-Phase Proteins - pharmacology; Animals; Antibody Formation; Anticoagulants - chemistry; Carrier Proteins - pharmacology; Chemical Precipitation; Drug Interactions; Female; Heparin - chemistry; Lipid A - analogs & derivatives; Lipid A - pharmacokinetics; Lipopolysaccharides - antagonists & inhibitors; Manganese - chemistry; Membrane Glycoproteins - pharmacology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Shock, Septic - drug therapy; Lipopolysaccharide; pharmacokinetics; lipid A analogue; lipopolysaccharide binding protein; E5564
• ISSN: 0968-0519
• DOI: 10.1177/09680519040100030501

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.