Isolated perfused liver as a tool to study the disposition of peptides, liver first-pass effects, and cell-specific drug delivery

Abstract

The isolated perfused liver technique has been widely used in drug disposition studies. This versatile methodology in which many experimental conditions can be easily manipulated, allows one to investigate the various rate limiting steps in peptide transport and drug metabolism: plasma flow, protein binding, sinusoidal membrane transport, as well as rate of metabolic conversion and biliary excretion. Plasma concentration profiles, biliary excretion rate patterns and tissue concentration data can be analyzed by proper pharmacokinetic fitting- and simulation programs. Mechanisms of transport (concentration-, ion- and ATP-dependency) and biotransformation (co-substrate availability, Vmax/Km values) as well as drug interactions at these levels can be more easily characterized compared with the intact animal. The presence of endothelial-, and fat storing cells as well as macrophages in this liver preparation also enables to test options of cell-specific drug targeting within the organ. Depending on terminal sugar and charge of (neo)-glycoprotein carriers, pharmacologically active agents can be delivered to the therapeutically relevant cell type. Examples of drug targeting to various liver cell types will be given: delivery of antiviral drugs to hepatocytes, targeting of anti-inflammatory and cytoprotective agents to macrophages in relation to inflammation, septic shock and liver fibrosis, as well as targeting of antineoplastic drugs and diagnostic agents. Some glycoproteins can be used for cell-specific targeting of antiviral drugs to macrophages (HIV). We developed glycoprotein carriers with a potent intrinsic anti-HIV activity that can be used for dual targeting (an effect of the carrier itself and the coupled drug at various levels of the replication cycle). Such drug targeting devices can also be used for delivery of antisense nucleotides and genes to reprogram various cell types in the body in vivo to produce therapeutic proteins.