DEVELOPMENT OF A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL FOR 2,4-DICHLOROPHENOXYACETIC ACID DOSIMETRY IN DISCRETE AREAS OF THE RABBIT BRAIN

A basic PBPK model for the dosimetry of organic acids in discrete area s of the brain was constructed using 2,4-D as a model compound. The PB PK model describes distribution of 2,4-D throughout the body and withi n discrete areas of the brain. The brain compartments in the model wer e the hypothalamus, caudate nucleus, hippocampus, forebrain, brainstem , and cerebellum. The remainder of the model consisted of two-body com partments and venous and arterial blood compartments. In the model, ch emical uptake by the brain was membrane-limited by the blood-brain bar rier (BBB) with saturable clearance from the cerebrospinal fluid (CSF) into the venous blood by the choroid plexus. The body has both a cent ral and a deep compartment with saturable clearance from the central c ompartment. The model was used to examine the brain and CSF concentrat ions of 2,4-D as a function of plasma 2,4-D, as well as plasma time-co urse behavior using experimental data from rabbits given 2,4-D 40 or 1 00 mg/kg,IP or Na-2,4-D 40 mg/kg, IV administration. Model parameters were adjusted to fit the observed 2,4-D concentrations in blood and br ain regions over a 2-h time frame. PBPK models could be a useful tool for evaluating the safety of this class of organic acids.