Pharmacokinetic and biodistribution profile of recombinant human interleukin-10 following intravenous administration in rats with extensive liver fibrosis.
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.
Rachmawati
Heni
H
Department of Pharmacokinetics and Drug Delivery, University Centre for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands. H.Rachmawati@farm.rug.nl
Beljaars
Leonie
L
Reker-Smit
Catharina
C
Van Loenen-Weemaes
Anne-miek M
AM
Hagens
Werner I
WI
Meijer
Dirk K F
DK
Poelstra
Klaas
K
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
D007457:Iodine Radioisotopes; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D011994:Recombinant Proteins; D016753:Interleukin-10