title: Pharmacokinetic and biodistribution profile of recombinant human interleukin-10 following intravenous administration in rats with extensive liver fibrosis.
abstract: OBJECTIVE
  Because interleukin-10 (IL-10) seems a promising new antifibrotic drug, we investigated the pharmacokinetic and biodistribution profile of this potent therapeutic cytokine in rats with extensive liver fibrosis (BDL-3). IL-10 receptor expression was also determined in relation to these aspects.
  
  
  METHODS
  To study the pharmacokinetic and biodistribution of IL-10, rhIL-10 was labeled with 125-iodine. Plasma samples of 125IrhIL-10 were obtained over a 30-min time period after administration of radiolabeled-cytokine to BDL-3 and normal rats. The tissue distribution was assessed 10 and 30 min after i.v. administration of 125IrhlL-10. IL-10 receptor expression was determined by immurohistochemical staining and RT-PCR technique.
  
  
  RESULTS
  . The 125IrhIL-10 plasma curves followed two-compartment kinetics with a lower AUC in BDL-3 rats as compared to control. Plasma clearance and distribution volume at steady state were larger in BDL-3 rats. Tissue distribution analysis in normal rats showed that 125IrhIL-10 highly accumulated in kidneys. In BDL-3 rats, the liver content of 125IrhIL-10 increased by a factor of 2, whereas kidney accumulation did not significantly change. Immunohistochemical staining and RT-PCR analysis showed that IL-10 receptor was clearly upregulated in BDL-3 rat livers.
  
  
  CONCLUSIONS
  . In normal rats, 125IrhIL-10 rapidly disappears from the circulation, and the kidney is predominantly responsible for this. In BDL-3 rats, the liver largely contributes to this rapid plasma disappearance, probably due to an increase in IL-10 receptor expression. The extensive renal clearance of IL-10 in vivo may limit a clinical application of this cytokine for the treatment of chronic liver diseases. To optimize the therapeutic effects of IL-10 in hepatic diseases, alternative approaches that either decrease renal disposition or that further enhance hepatic delivery should be considered.
authors.affiliation: Department of Pharmacokinetics and Drug Delivery, University Centre for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands. H.Rachmawati@farm.rug.nl
authors.forename: Heni
authors.initials: H
authors.lastname: Rachmawati
authors.forename: Leonie
authors.initials: L
authors.lastname: Beljaars
authors.forename: Catharina
authors.initials: C
authors.lastname: Reker-Smit
authors.forename: Anne-miek M
authors.initials: AM
authors.lastname: Van Loenen-Weemaes
authors.forename: Werner I
authors.initials: WI
authors.lastname: Hagens
authors.forename: Dirk K F
authors.initials: DK
authors.lastname: Meijer
authors.forename: Klaas
authors.initials: K
authors.lastname: Poelstra
mesh_terms: D000818:Animals; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007275:Injections, Intravenous; D016753:Interleukin-10 / Q000378:metabolism / Q000493:pharmacokinetics*; D007457:Iodine Radioisotopes; D007553:Isotope Labeling; D008103:Liver Cirrhosis / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000378:metabolism; D011994:Recombinant Proteins / Q000493:pharmacokinetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014018:Tissue Distribution
chemical_list: D007457:Iodine Radioisotopes; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D011994:Recombinant Proteins; D016753:Interleukin-10