Pharmacokinetics and disposition of recombinant human osteoprotegerin (rhOPG) after intravenous administration in female fischer rats

Osteoprotegerin (OPG) is a secreted member of the tumour necrosis factor receptor (TNFR) family that leads to the suppression of the differentiation, activation and survival of osteoclasts. The objective was to investigate the in vivo pharmacokinetics and tissue distribution of full-length recombinant human OPG (rhOPG) as well as its clearance mechanism using 125I-labelled protein (125I-rhOPG) after intravenous administration to female Fischer rats. 2. 125I-rhOPG was rapidly and predominantly distributed to the liver after dosing (3 mg kg−1). Immunohistochemical analysis indicated that rhOPG was located in the sinusoids of the liver. The hepatic uptake of 125I-rhOPG (0.01 mg kg−1) was partly regulated under a saturable process. Pre-dosing of some sulfated glycans (20 mg kg−1), especially dextran sulfate, heparin and fucoidan, markedly inhibited the hepatic uptake of 125I-rhOPG. The clearance of 125I-rhOPG was markedly reduced by the conjugation of dextran sulfate. The results suggested that the hepatic clearance of 125I-rhOPG was mainly mediated by the interaction with glycosaminoglycans.

[1]  Paolo Vicini,et al.  Population PK–PD model for Fc-osteoprotegerin in healthy postmenopausal women , 2008, Journal of Pharmacokinetics and Pharmacodynamics.

[2]  Frédéric Blanchard,et al.  Characterization of osteoprotegerin binding to glycosaminoglycans by surface plasmon resonance: Role in the interactions with receptor activator of nuclear factor κB ligand (RANKL) and RANK , 2006 .

[3]  S. Ricard-Blum,et al.  Characterization of osteoprotegerin binding to glycosaminoglycans by surface plasmon resonance: role in the interactions with receptor activator of nuclear factor kappaB ligand (RANKL) and RANK. , 2006, Biochemical and biophysical research communications.

[4]  J. Patsch,et al.  Syndecan-1 is involved in osteoprotegerin-induced chemotaxis in human peripheral blood monocytes. , 2005, The Journal of clinical endocrinology and metabolism.

[5]  S. Jurisson,et al.  Radioiodination of Rhenium Cyclized α-Melanocyte-Stimulating Hormone Resulting in Enhanced Radioactivity Localization and Retention in Melanoma , 2004, Cancer Research.

[6]  Steven W. Martin,et al.  Sustained Antiresorptive Effects After a Single Treatment With Human Recombinant Osteoprotegerin (OPG): A Pharmacodynamic and Pharmacokinetic Analysis in Rats , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[7]  Steven W. Martin,et al.  A Phase I study of AMGN‐0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases , 2003, Cancer.

[8]  T. Plesner,et al.  Osteoprotegerin is bound, internalized, and degraded by multiple myeloma cells. , 2002, Blood.

[9]  S. Mochizuki,et al.  Osteoclastogenesis inhibitory factor/osteoprotegerin ameliorates the decrease in both bone mineral density and bone strength in immobilized rats , 2002, Journal of Bone and Mineral Metabolism.

[10]  P. Kostenuik,et al.  OPG and PTH-(1–34) Have Additive Effects on Bone Density and Mechanical Strength in Osteopenic Ovariectomized Rats , 2001 .

[11]  C. Davis,et al.  Pharmacokinetics and tissue distribution of SB-251353, a novel human CXC chemokine, after intravenous administration to mice. , 2001, The Journal of pharmacology and experimental therapeutics.

[12]  A. Nakanishi,et al.  The Effect of a Single Dose of Osteoprotegerin in Postmenopausal Women , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[13]  P. Mantyh,et al.  Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord , 2000, Nature Medicine.

[14]  P. Kostenuik,et al.  Osteoprotegerin prevents and reverses hypercalcemia in a murine model of humoral hypercalcemia of malignancy. , 2000, Cancer research.

[15]  S. Morony,et al.  A Chimeric Form of Osteoprotegerin Inhibits Hypercalcemia and Bone Resorption Induced by IL‐1β, TNF‐α, PTH, PTHrP, and 1,25(OH)2D3 , 1999 .

[16]  K. Ikeda,et al.  Immunological Characterization of Circulating Osteoprotegerin/Osteoclastogenesis Inhibitory Factor: Increased Serum Concentrations in Postmenopausal Women with Osteoporosis , 1999, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[17]  S. Morony,et al.  Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[18]  S. Morony,et al.  A chimeric form of osteoprotegerin inhibits hypercalcemia and bone resorption induced by IL-1beta, TNF-alpha, PTH, PTHrP, and 1, 25(OH)2D3. , 1999, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[19]  Y. Courtois,et al.  In vivo involvement of heparan sulfate proteoglycan in the bioavailability, internalization, and catabolism of exogenous basic fibroblast growth factor. , 1999, Molecular pharmacology.

[20]  S. Mochizuki,et al.  Characterization of monomeric and homodimeric forms of osteoclastogenesis inhibitory factor. , 1998, Biochemical and biophysical research communications.

[21]  D. Lacey,et al.  Osteoprotegerin Ligand Is a Cytokine that Regulates Osteoclast Differentiation and Activation , 1998, Cell.

[22]  K Yano,et al.  Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[23]  S. Mochizuki,et al.  Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. , 1998, Endocrinology.

[24]  M. Goto,et al.  Characterization of Structural Domains of Human Osteoclastogenesis Inhibitory Factor* , 1998, The Journal of Biological Chemistry.

[25]  Y. Kato,et al.  Mechanism for the nonlinear pharmacokinetics of erythropoietin in rats. , 1997, The Journal of pharmacology and experimental therapeutics.

[26]  S. Mochizuki,et al.  Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis. , 1997, Biochemical and biophysical research communications.

[27]  G Shimamoto,et al.  Osteoprotegerin: A Novel Secreted Protein Involved in the Regulation of Bone Density , 1997, Cell.

[28]  R. Mahley,et al.  Intravenous heparinase inhibits remnant lipoprotein clearance from the plasma and uptake by the liver: in vivo role of heparan sulfate proteoglycans. , 1995, Journal of lipid research.

[29]  P. Godowski,et al.  The pharmacokinetics, tissue localization, and metabolic processing of recombinant human hepatocyte growth factor after intravenous administration in rats. , 1994, Endocrinology.

[30]  M. Hashida,et al.  Control of pharmaceutical properties of soybean trypsin inhibitor by conjugation with dextran. II: Biopharmaceutical and pharmacological properties. , 1989, Journal of pharmaceutical sciences.

[31]  M. Hashida,et al.  Control of pharmaceutical properties of soybean trypsin inhibitor by conjugation with dextran. I: Synthesis and characterization. , 1989, Journal of pharmaceutical sciences.