Skip to main content
SpringerLink
Log in

Pharmacokinetic and Biodistribution Profile of Recombinant Human Interleukin-10 Following Intravenous Administration in Rats with Extensive Liver Fibrosis

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose. 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 125IrhIL-10. IL-10 receptor expression was determined by immunohistochemical 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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

REFERENCES

  1. K. W. Moore, R. D. W. Malefyt, R. L. Coffman, and A. O'Garra. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19:683–765 (2001).

    PubMed  Google Scholar 

  2. D. Pajkrt, L. Camoglio, M. C. T. Buul, K. de Bruin, D. L. Cutler, M. B. Affrime, G. Rikken, T. van der Poll, J. W. ten Cate, and S. J. van Deventer. Attenuation of proinflammatory response by recombinant human IL-10 in human endotoxemia: effect of timing of recombinant human IL-10 administration. J. Immunol. 158: 3971–3977 (1997).

    PubMed  Google Scholar 

  3. M. Howard, A. O'Garra, H. Ishida, R. D. W. Malefyt, and J. de Vries. Biological properties of interleukin 10. J. Clin. Immunol. 12:239–247 (1992).

    PubMed  Google Scholar 

  4. K. Assadullah and H. D. Volk. Interleukin-10 therapy-review of a new approach. Pharmacol. Rev. 55:241–269 (2003).

    PubMed  Google Scholar 

  5. H. Louis, O. L. Moine, M. Goldman, and J. Deviere. Modulation of liver injury by interleukin-10. Acta Gastroenterol. Belg. 66:7–14 (2003).

    PubMed  Google Scholar 

  6. P. Knolle, J. Schlaak, A. Uhrig, P. Kempf, K. H. M. zum Buschenfelde, and G. Gerken. Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge. J. Hepatol. 22: 226–229 (1995).

    PubMed  Google Scholar 

  7. K. Thompson, J. Maltby, J. Fallowfield, M. McAulay, H. Mill-wardSadler, and N. Sheron. Interleukin-10 expression and func-tion in experimental murine liver inflammation and fibrosis. Hepatology 28:1597–1606 (1998).

    PubMed  Google Scholar 

  8. P. A. Knolle, A. Uhrig, U. Protzer, M. Trippler, R. Duchmann, K. H. M. zum Buschenfelde, and G. Gerken. Interleukin-10 ex-pression is autoregulated at the transcriptional level in human and murine Kupffer cells. Hepatology 27:93–99 (1998).

    PubMed  Google Scholar 

  9. K. C. Thompson, A. Trowern, A. Fowell, M. Marathe, C. Haycock, M. J. Arthur, and N. Sheron. Primary rat and mouse hepatic stellate cells express the macrophage inhibitor cytokine interleu-kin10 during the course of activation in vitro. Hepatology 28: 1518–1524 (1998).

    PubMed  Google Scholar 

  10. H. Louis, J. L. van Laethem, W. Wu, E. Quertinmont, C. Degraef, K. van den Berg, A. Demols, M. Goldman, O. Le Moine, and A. Geerts. and J. Deviere. Interleukin-10 controls neutro-philic infiltration, hepatocyte proliferation, and liver fibrosis induced by carbon tetrachloride in mice. Hepatology 28:1607–1615 (1998).

    PubMed  Google Scholar 

  11. S. C. Wang, M. Ohata, L. Schrum, R. A. Rippe, and H. Tsukamoto. Expression of interleukin-10 by in vitro and in vivo acti-vated hepatic stellate cells. J. Biol. Chem. 273:302–308 (1998).

    PubMed  Google Scholar 

  12. D. F. Fiorentino, A. Zlotnik, T. R. Mosmann, M. Howard, and A. O'Garra. IL-10 inhibits cytokine production by activated macrophages. J. Immunol. 147:3815–3822 (1991).

    PubMed  Google Scholar 

  13. P. Mathurin, S. Xiong, K. K. Kharbanda, N. Veal, T. Miyahara, K. Motomura, R. A. Rippe, M. G. Bachem, and H. Tsukamoto. IL-10 receptor and co-receptor expression in quiescent and activated hepatic stellate cells. Am. J. Physiol. Gastrointest. Liver Physiol. 282:G981–G990 (2002).

    PubMed  Google Scholar 

  14. R. M. Weber-Nordt, M. A. Meraz, and R. D. Schreiber. Lipo-polysaccharide-dependent induction of IL-10 receptor expression on murine fibroblasts. J. Immunol. 153:3734–3744 (1994).

    PubMed  Google Scholar 

  15. D. R. Nelson, G. Y. Lauwers, J. Y. N. Lau, and G. L. Davis. Interleukin 10 treatment reduces fibrosis in patients with chronic hepatitis C: A pilot trial of interferon nonresponders. Gastroenterology 118:655–660 (2000).

    PubMed  Google Scholar 

  16. D. R. Nelson, Z. Tu, C. Soldevila-Pico, M. Abdelmalek, H. Zhu, Y. L. Xu, R. Cabrera, C. Liu, and G. L. Davis. Long-term inter-leukin 10 therapy in chronic hepatitis C patients has a proviral and anti-inflammatory effect. Hepatology 38:859–868 (2003).

    PubMed  Google Scholar 

  17. R. D. Huhn, E. Radwanski, S. M. O'Connell, M. G. Sturgill, L. Clarke, R. P. Cody, M. B. Affrime, and D. L. Cutler. Pharmacokinetics and immunomodulatory properties of intravenously administered recombinant human interleukin-10 in healthy volunteers. Blood 87:699–705 (1996).

    PubMed  Google Scholar 

  18. S. R. Andersen, L. J. Lambrecht, S. K. Swan, D. L. Cutler, E. Radwanski, M. B. Affrime, and J. J. Garaud. Disposition of recombinant human interleukin-10 in subjects with various degrees of renal function. J. Clin. Pharmacol. 39:1015–1020 (1999).

    PubMed  Google Scholar 

  19. P. Chiu, E. Radwanski, G. Tetzloff, A. Monge, and S. Swanson. Interleukin-10 pharmacokinetics in intact and nephrectomized mice. Eur. Cytokine Netw. 7:67–69 (1996).

    PubMed  Google Scholar 

  20. E. Radwanski, A. Chakraborty, S. V. Wart, R. D. Huhn, D. L. Cutler, M. B. Affrime, and W. J. Jusko. Pharmacokinetics and leukocyte responses of recombinant human interleukin-10. Pharm. Res. 15:1895–1901 (1998).

    PubMed  Google Scholar 

  21. J. Kountouras, B. H. Billing, and P. J. Scheuer. Prolonged bile duct obstruction: a new experimental model for cirrhosis in the rat. Br. J. Exp. Pathol. 65:305–311 (1984).

    PubMed  Google Scholar 

  22. S. J. Mather and B. G. Ward. High efficiency iodination of mono-clonal antibodies for radiotherapy. J. Nucl. Med. 28:1034–1036 (1987).

    PubMed  Google Scholar 

  23. F. Mentre and R. Gomeni. A two-step interative algorithm for estimation in nonlinear mixed-effect models with an evaluation in population pharmacokinetics. J. Biopharm. Stat. 5:141–158 (1995).

    PubMed  Google Scholar 

  24. L. Beljaars, B. Weert, H. Bonnema, P. Olinga, G. M. Groothuis, G. Molema, D. K. F. Meijer, and K. Poelstra. Albumin modified with mannose 6-phosphate: a potential carrier for selective delivery of antifibrotic drugs to hepatic stellate cells. Hepatology 29: 1486–1493 (1999).

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacokinetics and Drug Delivery, University Centre for Pharmacy, University of Groningen, 9713, AV, Groningen, The Netherlands

    Heni Rachmawati, Leonie Beljaars, Catharina Reker-Smit, Anne-miek M. Van Loenen-Weemaes, Werner I. Hagens, Dirk K. F. Meijer & Klaas Poelstra

Authors
  1. Heni Rachmawati
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leonie Beljaars
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Catharina Reker-Smit
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anne-miek M. Van Loenen-Weemaes
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Werner I. Hagens
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dirk K. F. Meijer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Klaas Poelstra
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rachmawati, H., Beljaars, L., Reker-Smit, C. et al. Pharmacokinetic and Biodistribution Profile of Recombinant Human Interleukin-10 Following Intravenous Administration in Rats with Extensive Liver Fibrosis. Pharm Res 21, 2072–2078 (2004). https://doi.org/10.1023/B:PHAM.0000048199.94510.b0

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:PHAM.0000048199.94510.b0

Search

Navigation