Use of tissue disposition data from rats and dogs to determine species differences in input parameters for a...

Tissue disposition of perchloroethylene (PCE) was determined experimentally in two mammalian species of markedly different size in order to derive input parameters for the development of a physiologically based pharmacokinetic (PBPK) model, which could forecast the disposition of PCE in each species. Male Sprague-Dawley rats and male beagle dogs received a single bolus of 10 mg PCE/kg body wt in polyethylene glycol 400 by gavage. Serial samples of brain, liver, kidney, lung, heart, skeletal muscle, perirenal fat, and blood were taken for up to 72 hr following PCE administration. Blood and tissue PCE concentrations were analyzed using a gas chromatography headspace technique. Dogs exhibited considerably longer tissue and blood half-lives than did rats. The dogs also exhibited larger area under tissue concentration versus time curves for all tissues except the liver. Whole body clearance of PCE in the rat was greater than that in the dog. Model simulations indicated this could be attributed to more rapid and extensive PCE exhalation and metabolism by the rat. The in vivo blood:air partition coefficient determined for rats was similar to an in vitro value previously reported. In vivo tissue: blood partition coefficients, however, were 1.4 to 2.8 times greater than published in vitro values. The PCE in vivo blood:air partition coefficient for the dog was twice that of the rat, but tissue:blood partition coefficients were 1.5 to 3.0 times greater in the rat than in the dog. These results demonstrated the existence of significant differences in partition coefficients in two species commonly used in toxicity testing. The PBPK model was shown to have utility in predicting the impact of metabolism and exhalation on pharmacokinetics of PCE in different species of widely differing size.