Increase in Paracellular Permeability as a Pathophysiological Principle of Drug-Induced Intrahepatic Cholestasis in Rats

Abstract

Since the early studies on estrogen cholestasis (Forker, 1969), alterations in the permeability between canalicular and sinusoidal spaces have been regarded as a pathogenetic factor in drug-induced intrahepatic cholestasis. The general relevance of this alteration, however, was not clearly worked out. Isolated perfused livers pretreated with different drugs are a valuable tool to verify this concept. Thus, it was demonstrated that paracellular permeability to inert solutes such as sucrose and inulin was increased upon treating rats with α- naphthylisothiocyanate (ANIT, Krell et al., 1982) and estradiolvalerate (EV, Jaeschke et al., 1987a). Since it was observed that inert solutes were transported via transcellular pathways as well, quantitative determination was required of both transcellular and paracellular pathways of inert solutes into bile. This can be achieved by analyzing biliary off-kinetics of radioactive permeability markers after omission of the markers from the perfusion medium (Jaeschke et al., 1987b).