Targeting naproxen coupled to human serum albumin to nonparenchymal cells reduces endotoxin-induced mortality in rats with biliary cirrhosis.
Endotoxin is thought to play a major role in cirrhotic liver disease. Cyclo-oxygenase inhibitors were shown to be partially protective against endotoxin but cannot be used in cirrhotic patients because of renal side-effects. We argued that administration of naproxen (NAP) linked to human serum albumin (HSA), which results in specific delivery of NAP to endothelial cells (EC) and Kupffer cells (KC) and exhibited hepatoprotective effects against lipopolysaccharide (LPS) in vitro, could protect cirrhotic rats from LPS toxicity while preserving renal function. The studies were performed in rats rendered cirrhotic by bile duct ligation (BDL); animals received LPS (Escherichia coli, 800 microg/kg) intravenously. Five groups were studied: LPS alone, rats pretreated with a conventional dose of NAP (50 mg/kg), NAP-HSA (22 mg/kg), NAP equimolar to NAP-HSA (1.5 mg/kg), or the HSA carrier. LPS induced significant mortality (55%); this was not affected by equimolar NAP (57%) but accentuated by conventional NAP (88%). In contrast, NAP-HSA provided significant protection (9%; P < .05). After conventional NAP treatment, significant renal toxicity was observed as evidenced by a marked reduction in sodium excretion (LPS vs. NAP-HSA vs. NAP [50 mg/kg] 33 +/- 22 vs. 50 +/- 39 vs. 4 +/- 3 micromol/h; P < .05). Renal prostaglandin E2 (PGE2) excretion was reduced by NAP in all groups, but most markedly at the conventional dosage (LPS vs. NAP-HSA vs. NAP [50 mg/kg] 132 +/- 115 vs. 39 +/- 19 vs. 9 +/- 8 ng/mL; P < .05). Successful targeting was evidenced by a significant hepatic enrichment of NAP in the NAP-HSA group compared with the equimolar untargeted group (30.16 +/- 9.33 vs. 1.13 +/- 1.95 nmol/g liver). Thus, targeting NAP to EC/KC results in improved survival, higher efficacy, and sparing of renal function in cirrhotic rats.
Albrecht
C
C
Department of Clinical Pharmacology, University of Bern, Switzerland.
Meijer
D K
DK
Lebbe
C
C
Sägesser
H
H
Melgert
B N
BN
Poelstra
K
K
Reichen
J
J
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D015232:Dinoprostone / Q000652:urine; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004926:Escherichia coli; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D008105:Liver Cirrhosis, Biliary / Q000401:mortality / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D009288:Naproxen / Q000008:administration & dosage* / Q000031:analogs & derivatives; D051381:Rats; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000008:administration & dosage*; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004338:Drug Combinations; D008070:Lipopolysaccharides; D012709:Serum Albumin; D014409:Tumor Necrosis Factor-alpha; D009288:Naproxen; D015232:Dinoprostone