A B S T R A C T Perfused rat liver removes 97% of the taurocholate from the afferent circulation when the perfusate albumin concentration is 0.5 gIdl. Increasing the albumin concentration 10-fold reduces the concentration of free taurocholate by a factor of five but produces only a 50% reduction in the apparent uptake coefficient. A similar discrepancy is evident from a model-independent analysis ofthe extraction fractions. From these observations we argue that uptake is not driven solely, or even predominantly, by the plasma concentration of free taurocholate but also depends on interaction between albumin and the cell surface. Nonequilibrium binding, saturation kinetics, and an inhomogeneous population of liver cells are considered as alternative explanations and excluded. The possibility that albumin exerts its effect by enhancing the diffusion of taurocholate across an unstirred layer in the Disse space appears improbable but cannot be eliminated. INTRODUCTIONThe mammalian liver appears specialized for the removal of solutes bound to protein. The most obvious structural feature subserving this specialization is the porous endothelial lining of liver sinusoids, permitting rapid exchange of albumin between blood and the Disse space, thus ensuring intimate contact between bound solutes and the surface of liver cells. An endothelium permeable to protein can hardly explain the removal process itself, however, because albumin is not removed in the uptake process (1).No definitive study of this phenomenon has appeared, but it has generally been assumed that the plasma concentration of free (unbound) solute determines the uptake rate. Despite the fact that many solutes such as bilirubin and propranolol are efficiently

Summary. If water and inert solutes are assumed to pass from blood to bile through a fixed population of membrane pores, the changes in clearance pro--duced by dehydrocholate suggest that osmotic filtration rather than diffusion is the predominant mode of transfer for mannitol and erythritol. Bile produced in the canaliculi is modified in the interlobular ducts by the action of secretin. If distal fluid transfer is an important determinant of the choleresis evoked by dehydrocholate, the mechanism appears to effect a net secretion or reabsorption of fluid at a rate roughly proportional to the rate of flow in the canaliculi.

A B S T R A C T Rapid dissociation of organic anions from plasma albumin maximizes the presentation of free ligand to the cell surface and thus favors its efficient hepatic extraction. Even assuming these optimal conditions, however, taurocholate and rose bengal have hepatic extraction fractions that are higher than can be accounted for by spontaneous dissociation of their albumin-ligand complexes. In this study we developed a transport model that attributes this behavior to sites on the hepatocyte plasma membrane that bind the albumin-ligand complexes, promoting the transport of ligand into the hepatocyte. Fitting this model to rose bengal removal rates measured over a wide range of albumin concentrations yields estimates of the number of cell surface sites and their affinity for albumin. These estimates are in good agreement with those reported by Weisiger, Gollan, and Ockner for the binding of ligand-free albumin to isolated hepatocytes. We conclude that both experiments measure the same phenomenon and, accordingly, that the binding of albumin to the cell surface is the functional equivalent of albumin-mediated transport.

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It should be evident from this review of recent investigations that we are still very far from a consistent description of bile formation, much less a satisfactory understanding. Nevertheless certain broad conclusions emerge. Four distinct kinds of active solute transport can be identified, and because bile always has nearly the same osmotic pressure as plasma, each of them is a determinant of bile flow. 1. Concentrative transport of water-soluble organic constituents, of which bile acids are quantitatively most important, occurs in the canaliculi accompanied by the passive flow of water and inorganic electrolytes. Owing to micelle formation the osmotic force for this flow is largely attributable to Na+ ions that accompany the bile acids anions. 2. The canalicular flow obligated by the excretion of bile acids is supplemented by the entry of additional fluid, the so-called bile acid-independent canalicular fraction. Because no organic component has been identified to account for this phenomenon, the active transport of one or more inorganic ions is probably responsible. The limited evidence available at present suggests that Na+ ions is the most likely candidate. 3. The extralobular biliary epithelium can modify the flow and composition of bile by the reabsorption of inorganic ions--a process which resembles reabsorption from the gallbladder in the sense that bile in the lumen remains iso-osmotic with plasma while bile acids and the other organic constituents are concentrated. 4. Under the influence of secretin, and to a lesser degree other intestinal hormones, the ducts or ductules can secrete additional fluid in which HCO3- is concentrated with respect to plasma. A fifth component of bile is generated by the canalicular excretion of phospholipid and cholesterol, but these are insoluble in water and are incorporated into micelles, and, therefore exert no osmotic force. The existence of these processes is inferred from studies of many different species, and it should be emphasized that the picture is a composite one. For example, distal fluid reabsorption has been convincingly demonstrated only in dogs and monkeys, and secretin is not a choleretic in rats or rabbits. It should also be clear that the actual mechanisms of solute transport remain poorly defined. Thus the term active transport in the present context should be thought of in its general thermodynamic sense rather than as denoting any particular transport mechanism. For the future, the most pressing problems are methodologic. To mention only three that seem especially important: ways must be found to sample bile closer to its origin; the proper interpretation of studies with isolated liver cell membranes will require unambiguous methods to certify their source; and descriptions of transport kinetics must somehow be refined to reflect the effective intracellular concentration of solutes as well as their distribution within the liver lobule.