Pharmacokinetic modeling of disposition and time-course studies with [14C]atrazine.
A physiological pharmacokinetic (PPK) model, with blood, body, and brain compartments, was developed to estimate total plasma chlorotriazine (CI-TRI) time courses (i.e., atrazine [ATRA] and its three chlorinated metabolites) after oral dosing with ATRA. The model, based on disposition data for 14C-ATRA, tracked two pools of compounds: (1) ATRA and chlorinated metabolites (i.e., the CI-TRIs) and (2) glutathione conjugates. The PPK model developed from total radioactivity was valuable for assessing total plasma CI-TRI concentrations, estimating blood protein binding rates of CI-TRIs, and inferring relationships between tissue exposures of CI-TRIs and administered dose. Absorption of radioactivity into plasma was slow with a rate constant of 0.2 h-1. 14C-disposition data indicated that CI-TRIs react with red blood cells (presumably hemoglobin) and plasma proteins. Second-order rates of reaction of CI-TRIs with hemoglobin and plasma protein were estimated to be 0.008 L/mmol/h and 1.14 x 10(-7) L/mg/h, respectively. A time-course study, conducted as part of this study, evaluated the absorption, disposition, and elimination characteristics of individual CI-TRIs in plasma after a single oral dose of 90 mg ATRA/kg and indicated (1) that slow uptake into blood reflected both absorption and slow dissolution of the ATRA slurry and (2) that diaminochloro-s-triazine (DACT) was the major, persistent plasma CI-TRI after oral dosing. Optimally, PK model development for pesticide compounds like atrazine should include a combination of radiolabeled studies for residues and speciation studies of important metabolites.
McMullin
Tami S
TS
Department of Environmental and Radiological Health Sciences, Colorado State University, Ft. Collins, CO 80523, USA. mcmullin@colostate.edu
Brzezicki
Jill M
JM
Cranmer
Brian K
BK
Tessari
John D
JD
Andersen
Melvin E
ME
D000818:Animals; D001280:Atrazine / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001798:Blood Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000493:pharmacokinetics; D006540:Herbicides / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008954:Models, Biological; D051381:Rats; D013997:Time Factors
D001798:Blood Proteins; D006540:Herbicides; D005978:Glutathione; D001280:Atrazine