Elimination and tissue distribution of the monosaccharide lipid A precursor, lipid X, in mice and sheep.

Abstract

Lipid X (2,3-diacylglucosamine 1-phosphate) is a novel monosaccharide precursor of lipid A (the active moiety of gram-negative endotoxin) and has been found to be protective against endotoxin administered to mice and sheep and against life-threatening gram-negative infections in mice. Because of the need to design optimal dosing regimens in experimental models of ovine and murine septicemia, the pharmacokinetic profile of lipid X was investigated in sheep and in two strains of mice by using 32P-labeled lipid X. In sheep, peak whole blood lipid X levels after a bolus injection of 100 micrograms of lipid X per kg were 900 ng/ml. An initial rapid distribution phase of 7.98 +/- 0.1 min was observed, followed by a prolonged elimination phase of 3.0 +/- 0.5 h; the area under the curve from time zero to infinity was 428 +/- 27 ng.h/ml. The serum half-lives of lipid X were slightly shorter than whole blood half-lives, suggesting that lipid X associates with cellular elements. Metabolites of lipid X could not be detected in serum over a 4-h period. Lipid X appears to accumulate mainly in the liver, and the tissue distribution of lipid X resembles that of lipopolysaccharide. The elimination rate of lipid X in mice was approximately four times as rapid as that seen in sheep. Lipid X pharmacokinetics in lipopolysaccharide-sensitive DBA/2J mice were virtually identical with those seen in endotoxin-resistant C3H/HeJ mice. The pharmacokinetics described here should greatly aid in the design and interpretation of animal studies investigating the therapeutic applications of lipid X in gram-negative septicemia.

• Authors: D T Golenbock, S Ebert, J A Will, R A Proctor
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 32 Issue 1 Pg. 37-41 (Jan 1988) ISSN: 0066-4804 [Print] United States
• PMID: 3348611 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glycolipids
• Lipid A
• lipid X

Topics

• Animals
• Chemical Phenomena
• Chemistry
• Glycolipids (pharmacokinetics)
• Half-Life
• Lipid A (pharmacokinetics)
• Mice
• Mice, Inbred C3H (metabolism)
• Mice, Inbred DBA (metabolism)
• Sheep (metabolism)
• Tissue Distribution