The applicability of rat and human liver slices to the study of mechanisms of hepatic drug uptake

• Published in: Journal of pharmacological and toxicological methods 2001, Vol.45 (1), p.55-63
• Main Authors: Olinga, Peter, Hof, Ingrid H, Merema, Marjolijn T, Smit, Maaike, de Jager, Marina H, Swart, Piet J, Slooff, Maarten J.H, Meijer, Dirk K.F, Groothuis, Geny M.M
• Format: Article
• Language: English
• Subjects: Aconitic Acid - analogs & derivatives; Aconitic Acid - pharmacokinetics; Acridines - pharmacokinetics; Animals; Digoxin; Digoxin - pharmacokinetics; Electrochemistry; Endothelium - metabolism; Fluorescent Dyes - pharmacokinetics; Humans; In Vitro Techniques; Liver - cytology; Liver - drug effects; Liver - metabolism; Lucigenin; Male; Modified albumins; Pharmacokinetics; Rats; Rats, Wistar; Rhodamine B; Rhodamines - pharmacokinetics; Serum Albumin - pharmacokinetics; Serum Albumin, Human; Tissue Distribution
• ISSN: 1056-8719; 1873-488X
• DOI: 10.1016/S1056-8719(01)00127-7

In the present study we investigated the applicability of the liver slice model to study mechanisms of drug uptake. Four model compounds were investigated that enter hepatocytes via entirely different membrane transport mechanisms. Rhodamine B (RB), which enters hepatocytes by passive diffusion, was homogeneously distributed throughout the rat liver slice (250 μm thickness) within 5 min, indicating that the penetration rate into the slice and the diffusion rate into the cells are rapid. In contrast, lucigenin (LU), which is taken up by hepatocytes through adsorptive endocytosis, was detected in the inner cell layers after 15 min. Digoxin uptake into the slice showed a temperature-dependent component and was stereoselectively inhibited by quinine, which is compatible with the involvement of a carrier-mediated uptake mechanism. The neo-glycoalbumin Lactose 27-Human Serum Albumin (Lact 27-HSA) and the negatively charged Succinylated-Human Serum Albumin (Suc-HSA) entered the slices and were taken up temperature-dependently into hepatocytes and endothelial cells, respectively. The liver slice preparation is a valuable tool to investigate the mechanisms of cellular uptake of drugs. Moreover, the precision-cut liver slices offer the unique possibility to study both hepatocyte and endothelial cell function in human and rat liver.