Hepatic Clearance and Drug Metabolism Using Isolated Perfused Rat Liver

Abstract

The isolated perfused rat liver (IPRL) has been extensively used as an intact organ model for determination of hepatic clearance and metabolism of drugs. The IPRL model can also be applied to determine physiologically based pharmacokinetics. Since the IPRL model avoids neural and hormonal interferences and excludes influences from absorption processes and non-hepatic elimination routes such as renal excretion and respiration, it provides a relatively clean hepatic system to study metabolism and pharmacokinetics. It is especially useful to model the hepatic uptake associated with plasma protein binding and transport. The viability of the liver can be evaluated based on the gross appearance, bile flow, perfusion pressure, lactate dehydrogenase release, and oxygen uptake. The protocol describes the surgical procedures for isolation of the rat liver, a hemoglobin-free perfusion method, and application of this model for determination of hepatic uptake and clearance.