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

Abstract

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.

Pharmacokinetic Modeling of Hepatocyte Growth Factor in Experimental Animals and Humans

“…Several pharmacokinetic studies in rats have indicated that liver is the major clearance organ for HGF. [16][17][18][19] Therefore, the minimal change in pharmacokinetics in the ARF model (Fig. 2a, Table 1) can be explained by the minor contribution of the kidney to systemic clearance.…”

“…Pharmacokinetic data used for estimation of parameters were partly obtained in the present study in mice, and partly taken from previous studies in rats 18,19 and humans 24 , and preclinical studies in cynomolgus monkeys (Kringle Pharma…”

“…HGF is known to be eliminated via at least two types of specific receptor. [15][16][17][18] Therefore, we next attempted to construct mechanism-based pharmacokinetic model including receptor-mediated endocytosis ( Fig. S1) with an aim to understand pharmacokinetic mechanism.…”

“…A similar fitting procedure was also performed for reported pharmacokinetic data 18,19 obtained in rats. The plasma concentration profiles after bolus injection and during infusion in rats were simultaneously fitted to the model, and the fitted lines coincided well with the data (Fig.…”

“…For example, after down-regulation, i.e., reduction of the receptor density on the cell surface, induced by the injection of a relatively high dose of HGF, the total body clearance of 125 I-HGF first decreased, but subsequently increased due to recruitment of c-Met/HGF receptor to the cell surface. 15 A series of pharmacokinetic studies has clarified aspects of the pharmacokinetics of HGF in rats: (i) the liver is the major clearance organ for HGF; [16][17][18][19] (ii) the pharmacokinetics of HGF is nonlinear due to the presence of two saturable elimination mechanisms; 18,19 (iii) the high-and low-affinity elimination mechanisms have been identified as receptor-mediated endocytosis (RME) via c-Met/HGF receptor and endocytosis via cell-surface heparin-like substance, respectively. [15][16][17][18] The molecular mechanism of the latter elimination pathway is still unknown, but this elimination may be mediated by heparan-sulfate proteoglycans, which are known to bind HGF.…”