ISOLATED-PERFUSED LIVER AS A TOOL TO STUDY THE DISPOSITION OF PEPTIDES, LIVER FIRST-PASS EFFECTS, AND CELL-SPECIFIC DRUG-DELIVERY

The isolated perfused liver technique has been widely used in drug dis position studies. This versatile methodology in which many experimenta l 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 a s rate of metabolic conversion and biliary excretion. Plasma concentra tion profiles, biliary excretion rate patterns and tissue concentratio n data can be analyzed by proper pharmacokinetic fitting- and simulati on programs. Mechanisms of transport (concentration-, ion- and ATP-dep endency) and biotransformation (co-substrate availability, V-max/K-m v alues) as well as drug interactions at these levels can be more easily characterized compared with the intact animal. The presence of endoth elial-, and fat storing cells as well as macrophages in this liver pre paration also enables to test options of cell-specific drug targeting within the organ. Depending on terminal sugar and charge of (neo)-glyc oprotein 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 t o hepatocytes, targeting of anti-inflammatory and cytoprotective agent s to macrophages in relation to inflammation, septic shock and liver f ibrosis, as well as targeting of antineoplastic drugs and diagnostic a gents. Some glycoproteins can be used for cell-specific targeting of a ntiviral drugs to macrophages (HIV). We developed glycoprotein carrier s 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 var ious levels of the replication cycle). Such drug targeting devices can also be used for delivery of antisense nucleotides and genes to repro gram various cell types in the body in vivo to produce therapeutic pro teins.