title: 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.affiliation: Department of Medicine, Medical School, University of Wisconsin, Madison 53706.
authors.forename: D T
authors.initials: DT
authors.lastname: Golenbock
authors.forename: S
authors.initials: S
authors.lastname: Ebert
authors.forename: J A
authors.initials: JA
authors.lastname: Will
authors.forename: R A
authors.initials: RA
authors.lastname: Proctor
mesh_terms: D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D006017:Glycolipids / Q000493:pharmacokinetics*; D006207:Half-Life; D008050:Lipid A / Q000493:pharmacokinetics*; D051379:Mice; D008809:Mice, Inbred C3H / Q000378:metabolism*; D008811:Mice, Inbred DBA / Q000378:metabolism*; D012756:Sheep / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D006017:Glycolipids; D008050:Lipid A; C044283:lipid X