Development of a physiologically based pharmacokinetic model for 2,4-dichlorophenoxyacetic acid dosimetry in discrete areas of the rabbit brain.

Abstract

A basic PBPK model for the dosimetry of organic acids in discrete areas of the brain was constructed using 2,4-D as a model compound. The PBPK model describes distribution of 2,4-D throughout the body and within discrete areas of the brain. The brain compartments in the model were the hypothalamus, caudate nucleus, hippocampus, forebrain, brainstem, and cerebellum. The remainder of the model consisted of two-body compartments and venous and arterial blood compartments. In the model, chemical uptake by the brain was membrane-limited by the blood-brain barrier (BBB) with saturable clearance from the cerebrospinal fluid (CSF) into the venous blood by the choroid plexus. The body has both a central and a deep compartment with saturable clearance from the central compartment. The model was used to examine the brain and CSF concentrations of 2,4-D as a function of plasma 2,4-D, as well as plasma time-course behavior using experimental data from rabbits given 2,4-D 40 or 100 mg/kg, IP or Na-2,4-D 40 mg/kg, i.v. administration. Model parameters were adjusted to fit the observed 2,4-D concentrations in blood and brain regions over a 2-h time frame. PBPK models could be a useful tool for evaluating the safety of this class of organic acids.