Effect of electric charge on the hepatic uptake of macromolecules in the rat liver

Abstract

The effect of electric charge on the hepatic uptake of macromolecules was studied employing model macromolecules of identical molecular weight but differing in electrical charge. Rat liver was perfused using the single-pass method and model macromolecules were momentarily introduced into this system from the portal side. Outflow dilution patterns of model macromolecules were evaluated using statistical moment analysis. Anionic macromolecules were almost completely recovered in the outflow but cationic species showed a remarkable degree of hepatic uptake during the single passage. The values of the apparent retention volume ( V) of cationic macromolecules were greater than that of human serum albumin, indicating reversible interaction with tissue. Inhibition of hepatic uptake was observed among cationic macromolecules in the perfused liver. In the in vitro binding experiment with isolated rat hepatocytes, the association of cationic macromolecules occurred in a saturable manner and no significant difference was observed between incubation at 4 and 37° C. These results suggested that cationic macromolecules were adsorbed onto the hepatocyte surface by the effect of an electrostatic force. Thus, the electric charge of macromolecules was concluded as playing an important role in their hepatic uptake and is considered to offer a promising approach to controlling the pharmacokinetical characteristics of macromolecules.