Pharmacokinetic Modeling of Disposition and Time-Course Studies With [ 14 C]Atrazine

Abstract

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 14 C-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 m 1 . 14 C-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 2 10 m 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.