Organic anions can be excreted from the liver into the bile or back into the general circulation (sinusoidal efflux). It has previously been shown that the net sinusoidal efflux rate of dibromosulfophthalein from the perfused liver into the perfusate is the result of actual efflux from and reuptake into the liver, and can be strongly influenced by the presence of bovine serum albumin in the perfusion medium. The present study investigated whether the influence of albumin on the net sinusoidal efflux process is albumin-specific or whether other binding proteins could have a similar effect on the sinusoidal efflux. Using a single-pass liver perfusion technique and short-lasting (pulse) protein infusions, the stimulatory effect of a wide range of dibromosulfophthalein binding proteins on the sinusoidal efflux process were determined. These experiments showed that all the serum albumins tested as well as the liver cytosolic binding proteins fatty acid binding protein and ligandin (glutathione S-transferase) stimulated this process. The other proteins tested, bovine beta lactoglobulin-b, human gamma globulin and chicken egg lysozyme showed no stimulatory effect, despite relatively high equilibrium binding of dibromosulfophthalein. No clear-cut relationship was found between the equilibrium unbound ligand concentration as measured in perfusate and the stimulatory effect, suggesting absence of equilibrium binding in the sinusoids. Equilibrium binding of dibromosulfophthalein to chicken serum albumin and ligandin as well as the dissociation rate constants were determined in vitro with rapid filtration techniques. Pharmacokinetic modeling using a series compartment model showed that the stimulatory effect of these proteins could only be simulated accurately with higher values for both the association and dissociation rate constants compared with those determined in vitro, as was previously also found for bovine serum albumin. This may imply altered binding characteristics of the proteins during passage through the liver and/or a direct effect on the carrier-mediated efflux process. (C) Journal of Hepatology.