Physiologically Based Pharmacokinetic Modeling with Trichloroethylene and ItsMetabolite, Trichloroacetic Acid, in the Rat and Mouse

摘要

The uptake and metabolism of trichloroethylene (TCE), and the stoichiometricyield and kinetic behavior of one of its major metabolites, trichloroacetic acid (TCA), were compared in Fischer 344 rats and B6C3F1 mice using a physiological model. Physiologically based pharmacokinetic (PB-PK) model parameters (metabolic rate constants and tissue partition coefficients) were determined in male and female B6C3F1 mice and were taken from the literature for the male and female Fischer 344 rats. The kinetic behavior of TCA was described by a classical one-compartment model linked to a PB-PK model for TCE. The TCE blood/air partition coefficients for male and female mice, determined by vial equilibration, were 13.4 and 14.3. The Vmaxc values for male and female mice, using gas uptake techniques, were 32.7+0.1 mg/kg/h and the Km was 0.25 mg/liter. The PB-PK model for TCE adequately described the uptake and clearance of TCE in male and female rats exposed to a single, constant concentration of TCE vapor, but failed to describe the uptake and clearance of TCE in male and female mice exposed to a wide range TCE vapor concentrations. Computer predicted blood concentrations of TCE were generally greater than observed blood rations of TCE. inhalation, Trichloroethylene, Physiological Models.