Pharmacokinetic study of recombinant human hepatocyte growth factor administered in a bolus intravenously or via portal vein

Hepatocyte growth factor (HGF) stimulates liver regeneration and has the potential to be a therapeutic agent for fatal liver diseases, including fulminant hepatic failure and liver cirrhosis. In this study, we investigated the pharmacokinetics of recombinant human HGF, which will be soon available for clinical applications. When recombinant human HGF (0.1 mg/kg) was administered intravenously to normal rats, serum levels of human HGF increased to 89.7 +/- 20.6 ng/ml 5 min after the bolus injection, followed by a decrease with a half-life of 2.4 min. Recombinant HGF administered intravenously was distributed primarily to the liver and induced c-Met tyrosine phosphorylation in liver tissues. In comparison, rats given recombinant human HGF via the portal vein exhibited lower serum HGF and an increase in hepatic distribution. Additionally, when compared with normal rats, those with 70% partial hepatectomy or liver cirrhosis showed an increase in serum levels of human HGF with a prolonged half-life. These results suggest that, despite a short half-life, bolus injection of recombinant human HGF may induce therapeutic effect in patients with fatal live disease, and that the dose of this recombinant protein should be modulated according to the degree of liver injury. (C) 2004 Elsevier B.V. All rights reserved.