Pharmacokinetic analysis of the injured organ-specific targeting of hepatocyte growth factor

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Hepatocyte growth factor (HGF) is the potent mitogen for many types of epithelial cells and, therefore, is expected to be developed as therapeutics for the injured organs including the liver, kidney and lung. However, such a wide range of its biological activity for many types of cells may result in the side effects in the clinical stage. In the present study a steady-state pharmacokinetic analysis was performed to investigate the overall elimination and extraction of HGF by its target organs, including liver, kidney, and lung, during its constant intravenous infusion in rats. The plasma clearance of HGF became saturated as the steady-state plasma increased, but complete saturation was not achieved, even when the plasma concentration was much higher than the dissociation constant for the HGF receptor. Therefore, there is a low-affinity and high-capacity clearance mechanism, other than receptor-mediated endocytosis, involved in its elimination from the body. The hepatic extraction ratio of HGF, assessed by determining the HGF concentration in both the circulating blood and hepatic vein, was 40-60% while the HGF extraction both in kidney and lung was always less than 10%. Hepatic clearance accounted for approximately 70% of the plasma clearance. Thus, the present study shows that HGF in circulating plasma is efficiently extracted by the liver, compared with other HGF target organs. To observe the injured organ-specific biological activity the precursor (a single-chain form) of HGF was intravenously administered in the liver or kidney injured rats. The mitogenic activity assessed as the lableling index after injection of a single chain form was observed only in the injured organ whereas HGF exhibited its activity both in normal and injured organs. Thus, this approach may be one of the methods to observe its organ-specific activity in vivo.