Biologically-Based Kinetic Models for Chemical Kinetics in the Isolated Perfased Rat Liver system: BBKM-IPRLR (Basic Reclrculation Model for Water Soluble I Lipid Insoluble Chemicals (LOG Pow <0))

摘要

The objective of this report is to describe a generic biologically- based kinetic (BBK) model to simulate the kinetics of water soluble - lipid insoluble chemicals (log Po/w < 0) in the isolated perfused rat liver (IPRL) system. Such a model should have sufficient flexibility to allow for the inclusion of various physiological and biochemical processes into the description of the kinetics of chemicals that fall into this physical-chemical category. The following kinetic processes are incorporated into this model: (1) transport across cellular membranes, both at the sinusoidal-hepatocyte interface and the hepatocyte-biliary canalicular interface, (2) protein binding, both in perfusion medium and intracellular compartments of the liver, and (3) metabolism of the chemical in liver. The initial modeling efforts resulted in the development of a robust BBK model, named BBKM-IPRLR, that allows for the investigation of the effects of these kinetic process on the behavior of water soluble chemicals in the IPRL system. The generic model is used to demonstrate the effect of various kinetic processes on the observable state variables. Interactions between various kinetic processes are also demonstrated.