To examine whether a decrease in hepatic uptake, clearance or both of hepatocyte growth factor contributes to increased plasma hepatocyte growth factor levels, we kinetically analyzed hepatic hepatocyte growth factor handling using rats with carbon tetrachloride-induced liver injury in both in vivo and perfused liver systems. After the intravenous administration of tracer 125I-hepatocyte growth factor, the time profile of trichloroacetic acid-precipitable 125I-hepatocyte growth factor was analyzed, and tissue clearance and total body plasma clearance were determined. For the tissues examined (liver, kidney, lung, spleen and adrenal), liver and adrenal clearance of 125I-hepatocyte growth factor decreased significantly. It was found that the hepatic clearance explains the bulk of the total body plasma clearance. The hepatic clearance and the total body clearance decreased to minimums (approximately 40% of control) 24 hr after carbon tetrachloride administration and recovered to near-control values over a 6-day period. At 24 hr after carbon tetrachloride administration, a single-pass liver perfusion of 125I-hepatocyte growth factor was performed, and its results were compared with the control results. After a 15-min perfusion of 125I-hepatocyte growth factor, we washed the liver sequentially with heparin and then with acid buffer to separately determine the cell-surface-bound and internalized 125I-hepatocyte growth factor. In carbon tetrachloride-intoxicated rats, both the acid-washable binding and the internalized 125I-hepatocyte growth factor dropped to almost half of the control values, but the decrease in heparin-washable binding was minimal. In contrast, when 125I-hepatocyte growth factor was perfused with excess unlabeled hepatocyte growth factor (135 pmol/L), mostly saturating the cell-surface receptors, the change in cell-surface-bound 125I-hepatocyte growth factor and internalized 125I-hepatocyte growth factor in carbon tetrachloride-intoxicated rats was minimal. This finding, along with our previous finding that the cell-surface hepatocyte growth factor receptors are greatly down-regulated in carbon tetrachloride-intoxicated rats, suggests that the hepatic clearance of hepatocyte growth factor through receptor-mediated endocytosis decreases in carbon tetrachloride-intoxicated rats. The decrease in the hepatic clearance of hepatocyte growth factor could be one of the causes of the elevated hepatocyte growth factor level in the circulating blood in liver diseases.