Consequences of interaction of a lipophilic endotoxin antagonist with plasma lipoproteins

E5531, a novel synthetic lipid A analogue, antagonizes the toxic effects of lipopolysaccharide, making it a potential intravenously administered thera peutic agent for the treatment of sepsis. This report describes the distrib ution of E5531 in human blood and its activity when it is associated with d ifferent lipoprotein subclasses, After in vitro incubation of [C-14]E5531 w ith blood, the great majority (>92%) of material was found in the plasma fr action. Analysis by size-exclusion and affinity chromatographies and densit y gradient centrifugation indicates that [C-14]E5531 binds to lipoproteins, primarily high-density lipoproteins (HDLs), with distribution into low-den sity lipoproteins (LDLs) and very low density lipoproteins (VLDLs) being de pendent on the plasma LDL or VLDL cholesterol concentration. Similar result s were also seen in a limited study of [C-14]E5531 administration to human volunteers. The potency of E5531 in freshly drawn human blood directly corr elates to increasing LDL cholesterol levels. Finally, preincubation of E553 1 with plasma or purified lipoproteins indicated that binding to HDL result ed in a time-dependent loss of drug activity. This loss in activity was not observed,vith drug binding to LDLs or to VLDLs or chylomicrons, Taken toge ther, these results indicate that E5531 binds to plasma lipoproteins, makin g its long-term antagonistic potency dependent on the plasma lipoprotein co mposition.