Physiologically based pharmacokinetic model useful in prediction of the influence of species, dose, and exposure route on perchloroethylene pharmacokinetics.
The ability of a physiologically based pharmacokinetic (PBPK) model to predict the uptake and elimination of perchloroethylene (PCE) in venous blood was evaluated by comparison of model simulations with experimental data for two species, two routes of exposure, and three dosage levels. Unanesthetized male Sprague-Dawley rats and beagle dogs were administered 1, 3, or 10 mg PCE/kg body weight in polyethylene glycol 400 as a single bolus, either by gavage or by intraarterial (ia) injection. Serial blood samples were obtained from a jugular vein cannula for up to 96 h following dosing. The PCE concentrations were analyzed by headspace gas chromatography. For each dose and route of administration, terminal elimination half-lives in rats were shorter than in dogs, and areas under the blood concentration-time curve were smaller in rats than in dogs. Over a 10-fold range of doses, PCE blood levels in the rat were well predicted by the PBPK model following ia administration, and slightly underpredicted following oral administration. The PCE concentrations in dog blood were generally overpredicted, except for fairly precise predictions for the 3 mg/kg oral dose. These studies provide experimental evidence of the utility of the PBPK model for PCE in interspecies, route-to-route, and dose extrapolations.
Dallas
C E
CE
Department of Pharmacology and Toxicology, College of Pharmacy, University of Georgia, Athens 30602-2356.
Chen
X M
XM
Muralidhara
S
S
Varkonyi
P
P
Tackett
R L
RL
Bruckner
J V
JV
D000273:Adipose Tissue / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D002849:Chromatography, Gas; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D007269:Injections, Intra-Arterial; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D009132:Muscles / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013750:Tetrachloroethylene / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D014018:Tissue Distribution / Q000187:drug effects
D013750:Tetrachloroethylene