title: Heparin-hepatocyte growth factor complex with low plasma clearance and retained hepatocyte proliferating activity.
abstract: Because hepatocyte growth factor is known to have affinity for heparin, we studied the binding isotherm and found that hepatocyte growth factor has a high-affinity binding site for 35S-heparin with an equilibrium dissociation constant of approximately 0.6 nmol/L. We then analyzed the pharmacokinetic behavior of the heparin-hepatocyte growth factor complex in rats. The area under the plasma concentration-time profiles of trichloroacetic acid-precipitable radioactivities from 0 to 30 min after the intravenous administration of the heparin-125I-hepatocyte growth factor complex was approximately three times that after the administration of 125I-hepatocyte growth factor only. Because we previously demonstrated that the liver is the major clearance organ for hepatocyte growth factor, the hepatic uptake of 125I-hepatocyte growth factor and the heparin-125I-hepatocyte growth factor complex was compared. The liver-to-plasma concentration ratio after the intravenous administration of the complex was half that after the administration of 125I-hepatocyte growth factor only. Furthermore, the steady state hepatic extraction ratio of 125I-hepatocyte growth factor in perfused rat liver decreased depending on the heparin concentration. In addition, the biological activity of the complex was examined by assessing the 125I-deoxyuridine incorporation in cultured rat hepatocytes. Although the half-effective concentration of hepatocyte growth factor increased slightly--namely, two to three times in the presence of heparin compared with that in its absence--the maximal activity was not changed. We conclude that the heparin-hepatocyte growth factor complex, which retains biological activity, exhibits much lower clearances for hepatic uptake and plasma disappearance than hepatocyte growth factor itself.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kato
authors.forename: K X
authors.initials: KX
authors.lastname: Liu
authors.forename: T
authors.initials: T
authors.lastname: Nakamura
authors.forename: Y
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000818:Animals; D002455:Cell Division; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D006493:Heparin / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D066298:In Vitro Techniques; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D051381:Rats; D017208:Rats, Wistar
chemical_list: D017228:Hepatocyte Growth Factor; D006493:Heparin; D004247:DNA