A Physiologically Based Pharmacokinetic Model for Acrylamide and Its Metabolite, Glycidamide, in the Rat

Abstract

Acrylamide is a neurotoxicant and a multisite carcinogen in rats following chronic, high-dose exposures. In an effort to improve risk-based decisions for acrylamide (AMD) and its epoxide metabolite, glycidamide (GLY), a physiologically based pharmacokinetic (PBPK) model was developed for describing AMD and GLY kinetics in the rat. The PBPK model consists of components for both AMD and GLY. AMD is distributed within five compartments (arterial blood, venous blood, liver, lung, and all other tissues lumped together) and is linked to the GLY portion of the model via metabolism in the liver. GLY is distributed within the same five compartments. Dosing of AMD via the intravenous, intraperitoneal, or oral route of exposure is incorporated into the model structure. The model parameters include measured values for rat physiology (tissue volumes, blood flows), estimated tissue partition coefficients based on a published algorithm, and estimated values for metabolism and tissue binding based on fitting the model to tissue kinetic data from four studies. Despite gaps and limitations in the available database, a reliable description of the kinetics of AMD and GLY from existing studies was obtained using a single set of model parameters. The metabolism of AMD via cytochrome P-450 was best described using a V max of 1.6 mg/h/kg and a K m of 10 mg/L, while the metabolism of AMD via GST was described using a second-order rate constant of 0.55 L/h-mmol GSH. Similarly, the metabolism of GLY via epoxide hydrolase was best described using a V max of 1.9 mg/h/kg and a K m of 100 mg/L, while the metabolism of GLY via GST was described using a rate constant of 0.8 L/h-mmol GSH. These parameters were established based on the proportion of various metabolites found in urine. Future studies will need to focus on the collection of key data for refining model parameters for metabolism and tissue binding and for model validation, as well as for developing a similar model for humans. Completion of these additional studies will result in a validated rat and human PBPK model capable of predicting tissue doses linked to potential mechanisms of toxic effects for AMD and GLY and allow determination of scientifically defensible exposure limits that remain protective of human health.