A physiologically based pharmacokinetic and pharmacodynamic model to describe the oral dosing of rats with ethyl acrylate and its implications for risk assessment.
A physiologically based pharmacokinetic and pharmacodynamic model has been developed to describe the absorption, distribution, and metabolism of orally dosed ethyl acrylate. The model describes the metabolism of ethyl acrylate in 14 tissues based on in vitro metabolic studies conducted with tissue homogenates. The routes of metabolism included in the model are carboxylesterase-catalyzed ester hydrolysis, conjugation with glutathione, and binding to protein. To adequately describe the rate and extent of glutathione depletion following gavage dosing, the steady-state rate of glutathione synthesis in the organs of interest was included. In vivo validation of the model was conducted by comparing the predictions of the model to the results of a variety of gavage dosing experiments with ethyl acrylate, including (1) the time course of glutathione depletion in a variety of tissues up to 98 hr following dosing at three dose levels, (2) the rate and extent of radiolabeled carbon dioxide excretion, and (3) protein binding in the forestomach. The very rapid metabolism predicted by the model was consistent with the observation that ethyl acrylate was metabolized too rapidly in vivo to be detected by common analytical techniques for tissue metabolite analysis. The validation data indicated that the model provides a reasonable description of the pharmacokinetics and the pharmacodynamic response of specific rat tissues following gavage dosing of ethyl acrylate. A dose surrogate, or measure of delivered dose, for ethyl acrylate was calculated and correlated with the incidence and severity of contact site toxicity (edema, inflammation, ulceration, and hyperplasia). The model provides a quantitative tool for evaluating exposure scenarios for their potential to induce contact-site toxicity, and it provides a quantitative approach for understanding the lack of toxicity in tissues remote from the dosing site.
Frederick
C B
CB
Toxicology Department, Rohm and Haas Company, Spring House, Pennsylvania 19477.
Potter
D W
DW
Chang-Mateu
M I
MI
Andersen
M E
ME
D000179:Acrylates / Q000493:pharmacokinetics* / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D005978:Glutathione / Q000096:biosynthesis / Q000378:metabolism; D006868:Hydrolysis; D008658:Inactivation, Metabolic; D007700:Kinetics; D008297:Male; D008954:Models, Biological; D009153:Mutagens / Q000493:pharmacokinetics* / Q000494:pharmacology; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D012307:Risk Factors; D014018:Tissue Distribution
D000179:Acrylates; D009153:Mutagens; D011506:Proteins; D002245:Carbon Dioxide; C040833:ethyl acrylate; D002265:Carboxylic Ester Hydrolases; D005978:Glutathione