Pharmacokinetic modeling of 2, 4-dichlorophenoxyacetic acid (2,4-D) in rat and in rabbit brain following single dose administration

Abstract

A physiologically based pharmacokinetic (PBPK) model has been developed to describe the kinetics of organic anions in the central nervous system using 2,4-dichlorophenoxyacetic acid (2,4-D) as a model compound. The model consists of brain, body, venous, and arterial compartments. The brain compartment is subdivided into brain plasma, brain tissue and cerebrospinal fluid (CSF). Brain uptake is membrane-limited via a blood-brain barrier with saturable clearance from the CSF into the venous blood by the choroid plexus. The body has both a central and a deep compartment with saturable renal clearance from the central compartment. The model was used to examine venous plasma time course curves with experimental data from rats given 2,4-D by i.v. (5 or 90 mg/kg) or by oral ingestion (10, 50, or 150 mg/kg). The model was then extended to examine studies in which rabbit plasma, brain, and CSF concentrations were measured at 2 h after i.p. injection (40 mg/kg). In the rat, elimination was saturable (V max2 = 3.45 mg/h; K m2 = 86 mg/l) and the deep-compartment transfer coefficients were k 12 (0.013 l/h) and k 21 (0.048 l/h) between body and deep tissue compartment. Both oral and i.v. data were well described with these values. Limited single time point brain data from rabbits were analyzed with a lumped brain model assuming the generic model for 2, 4-D in rat applies to the rabbit. The model simulations were in good agreement with rabbit plasma, brain, and CSF concentrations at 2 h after i.p. injection.