title: LPS binding protein does not participate in the pharmacokinetics of E5564.
abstract: 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 [(14)C]-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 microg/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 wildtype 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.
authors.affiliation: Tsukuba Research Laboratories, Eisai Co Ltd, Ibaraki, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kaneko
authors.forename: Rika
authors.initials: R
authors.lastname: Ueda
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kawata
authors.forename: Sally
authors.initials: S
authors.lastname: Ishizaka
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yoshimura
mesh_terms: D000209:Acute-Phase Proteins / Q000494:pharmacology*; D000818:Animals; D000917:Antibody Formation; D000925:Anticoagulants / Q000737:chemistry; D002352:Carrier Proteins / Q000494:pharmacology*; D011232:Chemical Precipitation; D004347:Drug Interactions; D005260:Female; D006493:Heparin / Q000737:chemistry; D008050:Lipid A / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors*; D008345:Manganese / Q000737:chemistry; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012772:Shock, Septic / Q000188:drug therapy; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D000925:Anticoagulants; D002352:Carrier Proteins; D006493:Heparin; D008050:Lipid A; D008070:Lipopolysaccharides; D008345:Manganese; D008562:Membrane Glycoproteins; D000099231:Lipopolysaccharide-Binding Protein; C404742:E5564