title: The role of polymorphonuclear neutrophils (PMNs) in clearance of granulocyte colony-stimulating factor (G-CSF) in vivo and in vitro.
abstract: Previous studies have suggested that in vivo granulocyte colony-stimulating factor (G-CSF) pharmacokinetics may change over time. We studied three patients treated with high-dose chemotherapy followed by autologous bone marrow transplantation (ABMT) for metastatic breast cancer after intravenous administration of recombinant human (rh) G-CSF (5 or 16 microg/kg/day). We investigated plasma G-CSF concentrations and absolute neutrophil counts (ANCs/pL) in these patients on three separate days. G-CSF plasma clearance increased with time post-ABMT with no change in the apparent volume of distribution (Vd) of G-CSF. Regression analysis of G-CSF plasma clearance and ANCs revealed a linear relationship, with r2 = 0.85 (p = 0.00025). We further investigated this phenomenon in vitro by estimating pharmacokinetic parameters for rhG-CSF using a model in which polymorphonuclear neutrophils (PMNs) were incubated with rhG-CSF. We found that, at low G-CSF concentrations in vitro, there was an increase in G-CSF clearance with increasing ANCs, but at higher G-CSF concentrations this relationship did not hold. We suggest that this finding resulted from aggregation and polymerization of G-CSF at high concentrations when kept at 37 degrees C for 24-48 hours in vitro. Using fluorescence staining techniques, our data suggest there are changes over time in the amount of G-CSF bound to PMNs. These changes may reflect reexpression or recycling of the G-CSF receptor, and could explain the continuing clearance of G-CSF by PMNs in vitro. The strong positive correlation between G-CSF plasma clearance and ANCs in vivo is compatible with the hypothesis that neutrophils mediate one of the major pathways for rhG-CSF clearance.
authors.affiliation: Department of Medicine, West Virginia University, Morgantown 26506-9162, USA.
authors.forename: S G
authors.initials: SG
authors.lastname: Ericson
authors.forename: H
authors.initials: H
authors.lastname: Gao
authors.forename: G H
authors.initials: GH
authors.lastname: Gericke
authors.forename: L D
authors.initials: LD
authors.lastname: Lewis
mesh_terms: D016026:Bone Marrow Transplantation; D001943:Breast Neoplasms / Q000628:therapy; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000493:pharmacokinetics*; D006801:Humans; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism / Q000502:physiology*; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000493:pharmacokinetics; D014182:Transplantation, Autologous
chemical_list: D016188:Receptors, Granulocyte Colony-Stimulating Factor; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor