Existence of two nonlinear elimination mechanisms for hepatocyte growth factor in rats

Nonlinearity in the overall elimination of hepatocyte growth factor (HGF) was examined in rats. After intravenous administration, the plasma clearance (CLplasma) of HGF exhibited a dose-dependent biphasic reduction with high- and low-affinity components. If we consider our previous finding that both receptor-mediated endocytosis (RME) and a low-affinity uptake mechanism, probably mediated by heparan sulfate proteoglycan (HSPG), in the liver are major HGF clearance mechanisms, it may be that saturation of CLplasma at lower and higher doses represents saturation of RME and HSPG-mediated uptake, respectively. At an HGF dose (1.46 nmol/kg), which completely saturates the high-affinity component, CLplasma was almost completely reduced when HGF was premixed with heparin. However, CLplasma was reduced by heparin to, at most, one-fifth that after HGF alone in a dose near the linear range (3.66 pmol/kg). Saturation of CLplasma for HGF premixed with heparin was monophasic and nonlinear only at the lowest HGF doses. In vitro, high-affinity binding of [35S]heparin to HGF was found, showing that one HGF molecule binds to the penta- or hexasaccharide unit. Because mitogenic activity of HGF has been reported in the presence of heparin, these results suggest that heparin mainly inhibits low-affinity HGF uptake by complexing with HGF, whereas its effect on RME is relatively minor.