Abstract
Physiologically based pharmacokinetic (PBPK) modeling is an approach that has been used to predict successfully the pharmacokinetic disposition of numerous foreign chemicals. The accuracy of a PBPK model is dependent on the reliability of estimates of tissue/blood distribution coefficients (Kp) and appropriate kinetic constants descriptive of the elimination of the chemical under consideration. The present study evaluates the validity of the use of Kp values and kinetic constants determined in vitro for use in a PBPK model for the organothiophosphorus insecticide parathion. Kps were determined by equilibrium dialysis, whereas Vmaxs and Kms descriptive of the biotransformation of parathion were calculated from values determined previously in this laboratory. Using these kinetic constants to calculate a hepatic extraction ratio of parathion in the mouse yielded a value identical to that observed with mouse liver perfusions in situ performed previously in this laboratory. Use of Kp values and kinetic constants determined in vitro in a PBPK model accurately simulated levels of parathion in brain, lungs, blood, and liver up to 3 h after intravenous administration of this insecticide. This study demonstrates that chemical-specific parameters determined entirely in vitro can be used to construct accurate PBPK models.
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