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Toxicological Sciences 70, 27-39 (2002)
Copyright © 2002 by the Society of Toxicology

BIOTRANSFORMATION AND TOXICOKINETICS

Simulation of Trichloroacetic Acid Kinetics in the Isolated Perfused Rat Liver Using a Biologically Based Kinetic Model

Corike Toxopeus* and J. M. Frazier{dagger},1

* McLaughlin Research Institute, Great Falls, Montana 59405; and {dagger} Air Force Research Laboratory, Wright-Patterson Air Force Base, Ohio 45433-7400

Trichloroacetic acid (TCA) is a contaminant of drinking water. It induces peroxisome proliferation in livers of rats and mice and is hepatocarcinogenic in the latter species. Previous experimental studies of the kinetics of TCA in the isolated perfused rat liver (IPRL) at two doses have been reported. To gain more insight into the mechanistic processes controlling TCA kinetics in the liver a biologically based kinetic (BBK) model for the IPRL was used to analyze the experimental data. The IPRL was exposed to 25, 250, or 1000 µM TCA for 2 h in a recirculating perfusion system. These doses were not cytotoxic. The BBK model simulated the TCA concentration in perfusion medium and liver, and the biliary excretion of TCA. Separate protein binding studies showed that over 90% of TCA was bound to albumin in the perfusion medium whereas binding in liver homogenate was much lower. Integrating the information on protein binding into the BBK model, the hepatic uptake of TCA and its biliary excretion could be fitted assuming asymmetrical saturable transport at the sinusoidal membrane and linear transport at the bile canalicular membrane. To validate the BBK model, additional washout experiments were conducted in which the perfusion medium was replaced with TCA-free medium after 30 min of exposure of the liver to 1000 µM TCA. This approach illustrates the usefulness of BBK modeling for analyzing experimental kinetic data and gaining insight in kinetic mechanisms controlling the behavior of a chemical in the liver.

Key Words: TCA; isolated perfused rat liver; kinetics; modeling; transport parameters; protein binding.


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