CONSTRUCTION OF A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL FOR 2,4-DICHLOROPHENOXYACETIC ACID DOSIMETRY IN THE DEVELOPING RABBIT BRAIN

A physiologically based pharmacokinetic (PBPK) model that describes th e kinetics of organic anions by using 2,4-dichlorophenoxyacetic acid ( 2,4-D) as a representative compound was constructed for the developing rabbit brain at near-term pregnancy (Gestation Day 30). The model con sisted of brain, body, and venous and arterial compartments for the mo ther which were linked to the fetus by a placenta. Maternal brain comp artments in the model were brain plasma, cerebrospinal fluid (CSF), an d brain tissue including hypothalamus, caudate nucleus, hippocampus, f orebrain, brainstem, and cerebellum, The fetus consisted of brain, bod y, amniotic fluid, and venous and arterial compartments, The maternal body had both a central and a deep compartment; the fetal body had onl y one compartment, Maternal blood flow to the fetus was modeled as blo od flowing to the placenta, where it was equilibrated before it reache d the fetus. The brain uptake was membrane-limited by the blood-brain barrier, with saturable clearance from the CSF into the venous blood b y the choroid plexus in both fetus and mother. The model was used to c ompare concentrations of 2,4-D in maternal and fetal brain, maternal a nd fetal plasma, and amniotic fluid over time with experimental data f rom pregnant rabbits given 2,4-D intravenously (1, 10, or 40 mg/kg). T he model adequately simulated the 2-hr time course of 2,4-D concentrat ions in both mother and fetus. With continued development, this generi c PBPK model should be a useful tool for evaluating the safety of orga nic acid neurotoxicants in the developing brain. (C) 1996 Academic Pre ss, Inc.