Importance of the liver in plasma clearance of hepatocyte growth factors in rats

Abstract

After intravenous administration of 125I-labeled hepatocyte growth factor (HGF), trichloroacetic acid-precipitable radioactivity in the plasma disappeared rapidly with an early phase half-life of 4 min. The amounts of 125I-HGF distributed to the liver, adrenal, spleen, kidney, and lung tissues were much greater than those that could be accounted for by distribution to the extracellular space alone. The first-pass removal of 125I-HGF by the liver was approximately 26%; the liver accounted for approximately 70% of early-phase removal. The hepatic handling was also analyzed using a single-pass perfused liver system. The steady-state extraction ratio of tracer 125I-HGF was 0.48 but dropped to 0.23 in the presence of excess HGF (135 pM), demonstrating hepatic removal saturation of HGF. In the presence of excess HGF, the heparin-washable 125I-HGF, the heparin-resistant and acid-washable 125I-HGF, and the internalized 125I-HGF dropped to 54, 31, and 32% of the control values. The presence of at least two binding sites for HGF on the liver cell surfaces was made clear: the heparin-washable site and the heparin-resistant and acid-washable binding site, considered to have higher affinity for HGF. The internalization of 125I-HGF was observed to some extent even in the presence of excess HGF and phenylarsine oxide, known to be an inhibitor of polypeptides receptor-mediated endocytosis, suggesting the contribution of a relatively nonspecific internalization mechanism as well as receptor-mediated endocytosis.

Pharmacokinetic Modeling of Hepatocyte Growth Factor in Experimental Animals and Humans

“…Overall, the V p estimated by this fitting in rats and humans was close to the plasma volume (30~50 mL/kg) 25 and the reported value (52 mL/kg) obtained in rats, 16 but the values in mice and monkeys were higher ( Table 2). The V e in all species was much higher than the extracellular volume (10~20 mL/kg) 25 in the liver (Table 2).…”

“…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.…”

“…On the other hand, clearance of HGF has been suggested to be mediated by at least two binding sites, c-Met and cell-surface heparin-like substance. [16][17][18]31 Most of the data supporting the involvement of the two clearance sites were, however, obtained using systemically administered 125 I-labeled HGF as a tracer. [15][16][17]31 Thus, it has remained unclear whether the two sites are involved in HGF clearance over the same range of HGF concentrations.…”

“…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.…”

“…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.…”