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Antimicrobial Agents and Chemotherapy, March 2000, p. 504-510, Vol. 44, No. 3
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Consequences of Interaction of a Lipophilic Endotoxin Antagonist with Plasma Lipoproteins

Jeffrey R. Rose,1 Maureen A. Mullarkey,1 William J. Christ,2 Lynn D. Hawkins,2 Melvyn Lynn,3 Yoshito Kishi,4 Kishor M. Wasan,5 Kathy Peteherych,5 and Daniel P. Rossignol1,*

Biology Section1 and Chemistry Section,2 Eisai Research Institute of Boston, Inc., and Eisai Global Research,4 Andover, Massachusetts 01810; Eisai Inc., Glenpoint Center, Teaneck, New Jersey3; and Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada5

Received 18 June 1999/Returned for modification 10 October 1999/Accepted 29 November 1999

E5531, a novel synthetic lipid A analogue, antagonizes the toxic effects of lipopolysaccharide, making it a potential intravenously administered therapeutic agent for the treatment of sepsis. This report describes the distribution of E5531 in human blood and its activity when it is associated with different lipoprotein subclasses. After in vitro incubation of [14C]E5531 with blood, the great majority (>92%) of material was found in the plasma fraction. Analysis by size-exclusion and affinity chromatographies and density gradient centrifugation indicates that [14C]E5531 binds to lipoproteins, primarily high-density lipoproteins (HDLs), with distribution into low-density lipoproteins (LDLs) and very low density lipoproteins (VLDLs) being dependent on the plasma LDL or VLDL cholesterol concentration. Similar results were also seen in a limited study of [14C]E5531 administration to human volunteers. The potency of E5531 in freshly drawn human blood directly correlates to increasing LDL cholesterol levels. Finally, preincubation of E5531 with plasma or purified lipoproteins indicated that binding to HDL resulted in a time-dependent loss of drug activity. This loss in activity was not observed with drug binding to LDLs or to VLDLs or chylomicrons. Taken together, these results indicate that E5531 binds to plasma lipoproteins, making its long-term antagonistic potency dependent on the plasma lipoprotein composition.

* Corresponding author. Mailing address: Eisai Inc., Glenpointe Centre West 5th Floor, 500 Frank W. Burr Blvd., Teaneck, NJ 07666-6741. Phone: (201) 692-9160. Fax: (201) 692-0266. E-mail: dan_rossignol{at}eisai.com.

Antimicrobial Agents and Chemotherapy, March 2000, p. 504-510, Vol. 44, No. 3
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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