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 ,ug of lipid X per kg were 900 ng/mI. 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 lipopolysaccharidesensitive 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.Lipid X (2,3-diacylglucosamine 1-phosphate) ( Fig. 1) is an important monosaccharide precursor of lipid A (21), the toxic portion of gram-negative endotoxin (1). Although lipid X has some of the activities of lipopolysaccharide (LPS) (6,10,13,18,19,21,22,(26)(27)(28), it has little toxicity in laboratory animals (3,20). Postulating that lipid X might interfere with the toxic actions of endotoxin, Proctor et al. demonstrated that a single 750-,g dose of lipid X lowered mortality due to the administration of LPS in C57B1/10 mice (20); further studies in sheep have confirmed a protective effect of lipid X against LPS challenge (8). In addition to reducing mortality, lipid X significantly reduced LPS-induced pulmonary hypertension during both the early and late phases (8). Lipid X was also protective against fatal gramnegative infections in neutropenic mice (D. Golenbock, J. A. Leggett, W. A. Craig, C. R. H. Raetz, and R. A. Proctor, Program Abstr. 26th Intersci. Conf. Antimicrob. Agents Chemother., abstr. no. 555, 1986), indicating that lipid X might be a useful therapeutic compound for patients with serious, life-threatening gram-negative septicemia. The present studies of the elimination and distribution of lipid X were done to aid in designing optimal dosing regimens of lipid X in experimental septicemia. The results of our studies show that in sheep lipid X is rapidly distributed in the vascular tree and then slowly eliminated with a ha...

Effects of pretreatment with SDZ MRL 953, a novel immunostimulatory lipid A analog, on endotoxin-induced acute lung injury in guinea pigs

“…The elimination of lipid X following administra-tion of a bolus injection suggests that the LPS receptor of peripheral WBCs may be blocked by the administration of lipid A analogs 10 min before LPS challenge. However, receptor blockade could still be occurring at the tissue level 12 h after the administration of a lipid A analog on the basis of the results of the distribution of lipid X in tissue (6). Therefore, we speculate that although the mechanisms underlying the attenuating effects of SDZ on lung injury are still uncertain, immunopharmacological modulation leading to down regulation subsequent to LPS injection is more likely than receptor blockade.…”

“…We speculate that the attenuating effects of SDZ on lung injury may be mediated by immunopharmacological modulation, leading to down regulation of the response to subsequent LPS injection rather than receptor blocking. The pharmacokinetics of SDZ have not been demonstrated, although the elimination and tissue distribution of lipid X have been reported (6). The elimination of lipid X following administra-tion of a bolus injection suggests that the LPS receptor of peripheral WBCs may be blocked by the administration of lipid A analogs 10 min before LPS challenge.…”