title: Dexamethasone coupled to albumin is selectively taken up by rat nonparenchymal liver cells and attenuates LPS-induced activation of hepatic cells.
abstract: OBJECTIVE
  The human serum albumin (HSA) conjugate Dexa10-HSA was designed to specifically deliver the anti-inflammatory drug dexamethasone (Dexa) to nonparenchymal cells (NPC) in the rat liver. NPC play an important role in the pathogenesis of acute and chronic inflammatory liver diseases like fibrosis. Targeting Dexa to these cells might reduce its adverse effects and increase the efficacy.
  
  
  METHODS
  Tissue and intrahepatic distributions of Dexa10-HSA were assessed in normal and fibrotic rats with 125I-labelled conjugate and by immunohistochemistry. The effect of the conjugate on lipopolysaccharide (LPS)-induced inflammation and cell activation was studied in vitro with precision-cut liver slices and in vivo.
  
  
  RESULTS
  Ten minutes after i.v. injection 72+/-13% and 65+/-12% of a tracer dose of Dexa10-HSA had been taken up in normal and fibrotic livers, respectively. Unconjugated Dexa also accumulated in livers, but cellular distribution studies revealed an accumulation in parenchymal cells (NPC vs. parenchymal cell (PC) ratio=0.29+/-11, p<0.005) whereas Dexa10-HSA accumulated in nonparenchymal cells (NPC/PC ratio=7.9+/-3.1). Both coupled and uncoupled Dexa showed effective inhibition of LPS-induced NOx and TNFalpha production in precision-cut liver slices. At low concentrations (0.02 microM), however, Dexa10-HSA was more efficient at inhibiting TNFalpha production than uncoupled Dexa. In fibrotic rats Dexa10-HSA (3 mg/kg) and an equimolar amount of uncoupled Dexa (0.22 mg/kg) both significantly promoted survival after LPS-induced acute inflammation.
  
  
  CONCLUSIONS
  Dexa10-HSA was at least as effective as uncoupled Dexa at inhibiting LPS-induced effects, which indicates that HSA-bound Dexa is pharmacologically active. Coupling Dexa to HSA shifted the accumulation of Dexa from the PC to the NPC of livers. Since mediator release from NPC is crucial in the initiation and propagation of the fibrotic process, selective delivery of Dexa in NPC may improve the efficacy and safety of corticosteroid treatment of liver fibrosis.
authors.affiliation: Groningen University Institute for Drug Exploration, Department of Pharmacokinetics and Drug Delivery, University of Groningen, The Netherlands. B.Melgert@farm.rug.nl
authors.forename: B N
authors.initials: BN
authors.lastname: Melgert
authors.forename: P
authors.initials: P
authors.lastname: Olinga
authors.forename: V K
authors.initials: VK
authors.lastname: Jack
authors.forename: G
authors.initials: G
authors.lastname: Molema
authors.forename: D K
authors.initials: DK
authors.lastname: Meijer
authors.forename: K
authors.initials: K
authors.lastname: Poelstra
mesh_terms: D000418:Albumins / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D003239:Connective Tissue Cells / Q000378:metabolism; D003907:Dexamethasone / Q000378:metabolism* / Q000494:pharmacology; D005938:Glucocorticoids / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000418:Albumins; D005938:Glucocorticoids; D003907:Dexamethasone