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: Kazuhiro Kaneko, Rika Ueda, Tsutomu Kawata, Sally Ishizaka, Tsutomu Yoshimura
• Journal: Journal of endotoxin research (J Endotoxin Res) Vol. 10 Issue 3 Pg. 185-94 ( 2004) ISSN: 0968-0519 [Print] United States
• PMID: 15198853 (Publication Type: Journal Article)

Chemical References

• Acute-Phase Proteins
• Anticoagulants
• Carrier Proteins
• E5564
• Lipid A
• Lipopolysaccharides
• Membrane Glycoproteins
• lipopolysaccharide-binding protein
• Manganese
• Heparin

Topics

• Acute-Phase Proteins (pharmacology)
• Animals
• Antibody Formation
• Anticoagulants (chemistry)
• Carrier Proteins (pharmacology)
• Chemical Precipitation
• Drug Interactions
• Female
• Heparin (chemistry)
• Lipid A (analogs & derivatives, pharmacokinetics)
• Lipopolysaccharides (antagonists & inhibitors)
• Manganese (chemistry)
• Membrane Glycoproteins (pharmacology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Shock, Septic (drug therapy)