L/kg iron). One, 3, 7, and 14 days post-PH, clearance var-The hepatic asialoglycoprotein receptor is responsible ied with dose, suggesting ASGP receptor saturation. As for rapid clearance of desiaylated glycoproteins from regeneration proceeded, the dose of contrast agent the circulation by receptor-mediated endocytosis. Previneeded to cause a deviation from first-order kinetics inous in vitro studies in hepatocyte preparations from rats creased, suggesting gradual recovery of ASGP receptor subjected to partial hepatectomy (PH) of 70% to stimufunction. Hepatic relaxation was determined by in vitro late hepatic regeneration showed decreased asialoglycospectroscopy 60 minutes after administration of graded protein (ASGP) receptor binding. We used an ASGP redoses of BMS 180550 and showed dose-dependent inceptor-targeted hepatic magnetic resonance imaging creases in relaxation. Kinetic analysis at 1 day post-PH (MRI) agent, BMS 180550, to demonstrate similar demonstrated a decrease in the apparent k m and the changes in receptor biology in vivo. BMS 180550 is an maximum response, R max , suggesting a decrease in the arabinogalactan-coated ultrasmall superparamagnetic number of functional asialoglycoprotein receptors with iron oxide preparation. Arabinogalactan is a ligand for concomitant increase in receptor affinity. Systemic enthe ASGP receptor and, thereby, targets the contrast dotoxemia, which normally accompanies hepatic regenagent exclusively to hepatocytes. Hepatic uptake of BMS eration induced by PH, also decreased clearance of BMS 180550 was assessed by sequential precontrast and post-180550 and slowed hepatic uptake of the contrast agent. contrast MRI in rats subjected to PH of 70%. In regener-Altered BMS 180550 pharmacokinetics in endotoxinating liver 1 and 3 days after PH, the maximum decrease treated rats was enhanced by prior administration of in hepatic signal intensity (62.2% { 6.1 and 59.4% { 3.8, small doses of competing ligand. Our studies document respectively) was significantly less than the maximum the value of BMS 180550 in following changes in ASGP decrease seen in sham-operated animals at 1 and 3 days function that accompany PH or systemic endotoxemia. postsurgery (39.5% { 2.5 and 44% { 1.0, respectively). The This agent may be useful in assessing the degree of hetime necessary to reach 80% of the maximum decrease in patic regeneration in patients with clinical liver disease. hepatic signal intensity, (t 80 ), was less than 2 minutes in (HEPATOLOGY 1996;23:1631-1641.) control rats and increased to 7.5 { 1.3 min and 11.0 { 2.3 minutes at 1 and 3 days post-PH, respectively. By 7 days post-PH, contrast-enhanced MRI no longer de-
Hepatic regeneration induced chemically or surgitected a difference in regenerating liver. Because BMS cally stimulates the normally quiescent liver to un-180550 is taken up exclusively by the liver, clearance of dergo a wave of cell proliferation leading to restoration the agent from the blood was used as a measure of heof hepatic mass within a few days. 1 Clinically, hepatic patic clearance. Concentration-time curves constructed regeneration is necessary to replace hepatocytes lost by measuring changes in blood T2 after an intravenous by tissue necrosis in acute liver injury. [2][3][4][5][6][7] The adequacy dose of BMS 180550 were used to determine clearance of this regenerative response is an important factor of the agent. Blood clearance of BMS 180550 in normal that separates nonfulminant from fulminant hepatiliver (15.4 { 1.08 mL/min) obeyed first-order kinetics and did not vary over the dose range tested (10 to 100 mmol/ tis. 8 A technique permitting quantifiable assessment of hepatic regeneration in acute liver injury might, therefore, provide valuable prognostic information and aid in determining the need for hepatic transplantation.