Efficient extraction by the liver governs overall elimination of hepatocyte growth factor in rats

A steady-state pharmacokinetic analysis was performed to investigate the overall elimination and extraction of hepatocyte growth factor (HGF) by its target organs, including liver, kidney, and lung, during its constant i.v. infusion in rats. The plasma clearance of HGF became saturated as the steady-state plasma concentration (Cpss) increased, but complete saturation was not achieved, even when the Cpss ( approximately 1000 pM) was much higher than the dissociation constant for the HGF receptor (20-40 pM), which has been identified as one of the major clearance sites for HGF. This result suggests that 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 to 60%, whereas the HGF extraction both in kidney and lung was always less than 10%. Hepatic clearance accounted for approximately 70% of the plasma clearance at any Cpss. Thus, the present study shows that HGF in circulating plasma is efficiently extracted by the liver compared with other HGF target organs, the liver being involved in 70% of the overall elimination both under linear and nonlinear conditions. Biliary excretion of HGF was observed, but this accounted for only 0.1 to 0. 2% of the infusion rate, indicating that the nonlysosomal pathway of HGF, which avoids the lysosomal enzymes and transcytoses HGF directly into the bile, is very minor indeed.