Intraportal administration of low-dose recombinant human hepatocyte growth factor enhances effects of hepatocellular transplantation.

Background/Aims: Although recombinant human hepatocyte growth factor (rhHGF) is a potent mitogen, the dose used for patients is still not clear and must be low to avoid untoward effects. Firstly, the optimal strategy of the dose and route of rhHGF was investigated. Secondly, low-dose rhHGF, which would induce proliferation of transplanted hepatocytes, was explored using Nagase analbuminemic rats. Methodology: 1) Concentrations of rhHGF in the portal vein were measured after continuous administration of titrated rhHGF through the jugular vein or portal vein. 2) F344 rat hepatocytes (2x10 7 cells) were transplanted in the liver of Nagase analbuminemic rats. On the 7th day, the rats were subjected to a low-dose rhHGF treatment. Results: When the rats were given rhHGF in a dose of 50μg/kg/day, the mean concentration in the portal vein (0.8±0.1ng/mL) was almost similar to the minimum concentration which stimulated hepatocyte proliferation in vitro. When low-dose rhHGF (50μg/kg/day) was administered directly into the portal vein following hepatocyte transplantation in Nagase analbuminemic rats, the serum levels of albumin were significantly higher than in other groups. It was found that the concentration of rhHGF in the portal vein were 3.1±0.5ng/mL with continuous intraportal infustion and 0.8±0.1ng/mL with continuous systemic infusion. Conclusions: It was found that the minimal dose of rhHGF needed to stimulate hepatocyte proliferation was 50μg/kg/day. With rhHGF (50μg/kg/day), continuous intraportal infusion afforded a more favorable outcome in case of proliferation of hepatocytes.