Development of a physiologically based pharmacokinetic model for perchloroethylene using tissue concentration-time data.
The tissue disposition of perchloroethylene (PCE) was characterized experimentally in rats in order to (1) obtain input parameters from in vivo data for the development of a physiologically based pharmacokinetic (PBPK) model, and (2) use the PBPK model to predict the deposition of PCE in a variety of tissues following inhalation exposure. For the derivation of model input parameters, male Sprague-Dawley rats received a single bolus of 10 mg PCE/kg body wt in polyethylene glycol 400 by ia injection through an indwelling carotid arterial cannula. Other male Sprague-Dawley rats inhaled 500 ppm PCE for 2 hr in dynamic exposure inhalation chambers. Serial samples of brain, liver, kidney, lung, heart, skeletal muscle, perirenal fat, and blood were taken for up to 72 hr following ia injection, during the 2-hr inhalation exposure, and for up to 72 hr postexposure. Blood and tissue PCE concentrations were analyzed using a gas chromatography headspace technique. Following ia administration, the tissues exhibited similar terminal elimination half-lives (t1/2). As comparable tissue t1/2 are consistent with a blood-flow-limited model, tissue:blood partition coefficients were calculated for noneliminating compartments by division of the area under the tissue concentration-time curve (AUC) by the blood AUC. Liver PCE concentration versus time data were employed in the calculation of in vivo metabolic rate constants. A PBPK model was developed using these parameters derived from the ia data set and used to predict tissue PCE concentrations during and following PCE inhalation. Predicted tissue levels were in close agreement with the levels measured over time in the seven tissues and in blood. Tissue concentration-time data can thus provide valuable input for parameter estimation and for validation of PBPK model simulations, as long as independent in vivo data sets are used for each step.
Dallas
C E
CE
Department of Pharmacology and Toxicology, College of Pharmacy, University of Georgia, Athens 30602-2356.
Chen
X M
XM
O'Barr
K
K
Muralidhara
S
S
Varkonyi
P
P
Bruckner
J V
JV
D000280:Administration, Inhalation; D000818:Animals; D001273:Atmosphere Exposure Chambers; D002849:Chromatography, Gas; D006207:Half-Life; D007269:Injections, Intra-Arterial; D008297:Male; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D013750:Tetrachloroethylene / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors; D014018:Tissue Distribution
D013750:Tetrachloroethylene