Prior studies into the mechanism of the hepatic uptake of organic anions have generally been interpreted in terms of transport across the plasma membrane. However, recent work by ourselves and others now suggests that other steps in the uptake process such as the transfer of organic anions from serum albumin to the plasma membrane and from the plasma membrane to cytoplasmic sites of sequestration may be equally important in determining the rate of hepatic clearance. These processes have not yet been systematically investigated. Two specific questions will be addressed. First, is dissociation of the organic anion from albumin spontaneous or is it catalyzed by the liver cell? Preliminary data suggest that spontaneous dissociation may be too slow to account for the observed rates of hepatic uptake for many organic anions, and saturable binding sites for albumin have been detected on the hepatocyte surface which may catalyze the dissociation process. Second, is the uptake rate determined by membrane or cytoplasmic transport? Recent data suggest that diffusion through the cytoplasm may limit the rate of uptake, and that this process, which is catalyzed by soluble organic anion binding proteins, can account for all the kinetic features of carrier-mediated transport which characterize organic anion uptake. These studies will be greatly facilitated by the use of a newly developed perfused rat liver model to generate kinetic data. This single-pass system permits rapid determination of highly precise uptake rates under steady-state conditions, making it feasible to study many previously uninvestigated factors which now appear of critical importance for hepatic uptake. The information to be obtained is essential for an understanding of important hepatic functions, such as hormonal regulation of fatty acid uptake and very low density lipoprotein production and the clearance and detoxification of anionic drugs, toxins, carcinogens and bilirubin. Moreover, it will permit a more complete understanding of the hepatic transport defects in common conditions such as Gilbert's syndrome, hepatitis and cirrhosis.
