Pharmacokinetic modeling of 2,4-dichlorophenoxyacetic acid (2,4-D) in rat and in rabbit brain following single dose administration.
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 (Vmax2 = 3.45 mg/h; Km2 = 86 mg/l) and the deep-compartment transfer coefficients were K12 (0.013 l/h) and K21 (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.
Kim
C S
CS
Division of Toxicological Research, Food and Drug Administration, Washington, D.C. 20204.
Gargas
M L
ML
Andersen
M E
ME
D015084:2,4-Dichlorophenoxyacetic Acid / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D002831:Choroid Plexus / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D008954:Models, Biological; D009498:Neurotoxins / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D011817:Rabbits; D051381:Rats; D011916:Rats, Inbred F344
D009498:Neurotoxins; D015084:2,4-Dichlorophenoxyacetic Acid