Pharmacokinetics and pharmacological effect of recombinant human granulocyte colony-stimulating factor conjugated to poly(styrene-co-maleic acid) in rats.
A new derivative of recombinant human granulocyte colony-stimulating factor (rhG-CSF) has been synthesized by conjugating rhG-CSF to poly(styrene-co-maleic acid) (poly(styrene-co-maleic acid)-rhG-CSF) to try to avoid glomerular filtration and thus potentiate the neutrophil-proliferating activity of rhG-CSF. Poly(styrene-co-maleic acid)-rhG-CSF was highly bound to bovine serum albumin (BSA) and the molecular weight of the poly(styrene-co-maleic acid)-rhG-CSF-BSA complex was estimated to be about 90000 by gel filtration. Intravenous administration of poly(styrene-co-maleic acid)-rhG-CSF to normal rats resulted in a dose-dependent increase in neutrophil count. The neutrophil-proliferating activity of poly(styrene-co-maleic acid)-rhG-CSF was about 10 times greater than that of rhG-CSF. After intravenous injection at a dose of 5 microg protein kg(-1) the total clearance of rhG-CSF fell from 71.0 to 32.1 mLh(-1) kg(-1) following poly(styrene-co-maleic acid) modification. An isolated perfusion study in rat kidney showed that the filtered fraction of rhG-CSF was reduced by conjugation with poly(styrene-co-maleic acid). These results suggest that poly(styrene-co-maleic acid)-conjugation can potentiate the neutrophil-proliferating activity of rhG-CSF by reducing, at least in part, its renal clearance.
Kunimasa
J I
JI
Department of Pharmacy, Kyoto University Hospital, Kyoto University, Japan.
Itoga
Y
Y
Yasuhara
M
M
Hori
R
R
Inui
K I
KI
D000818:Animals; D019540:Area Under Curve; D003432:Cross-Linking Reagents; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D007668:Kidney / Q000378:metabolism; D008297:Male; D008298:Maleates / Q000008:administration & dosage* / Q000097:blood; D008657:Metabolic Clearance Rate; D011137:Polystyrenes / Q000008:administration & dosage* / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution
D003432:Cross-Linking Reagents; D008298:Maleates; D011137:Polystyrenes; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C059316:poly(styrene-co-maleic acid)butyl ester