A Physiologically Based Pharmacokinetic/Pharmacodynamic Model for Carbofuran in Sprague-Dawley Rats Using the Exposure-Related Dose Estimating Model

• DOI: 10.1093/toxsci/kfm232
• Publication Date: 2007-09-05T21:41:14Z
• Authors: Xiaofei Zhang; Andy M. Tsang; Miles S. Okino; Frederick W. Power; James B. Knaak; Lynda S. Harrison; Curtis C. Dary
• Keywords: Carbofuran

Carbofuran (2,3-dihydro-2,2-dimethyl-7-benzofuranyl-N-methylcarbamate), a broad spectrum N-methyl carbamate insecticide, and its metabolite, 3-hydroxycarbofuran, exert their toxicity by reversibly inhibiting acetylcholinesterase (AChE). To characterize AChE inhibition from carbofuran exposure, physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model was developed in the Exposure-Related Dose Estimating Model (ERDEM) platform for Sprague-Dawley (SD) rat. Experimental estimates of physiological, biochemical, physicochemical parameters were obtained or on data open literature. The PBPK/PD structure included metabolism liver to 16 known metabolites, enterohepatic circulation glucuronic acid conjugates, excretion urine feces. Bolus doses ingestion 50 μg/kg 0.5 mg/kg simulated blood brain activity. ERDEM half-life 5.2 h urinary clearance, experimental activity reproduced brain. Thirty found influential outputs chosen perturbation Monte Carlo simulations evaluate impact variability predictions. Results simulation runs indicated that minimum ranged 29.3 79.0% (as 5th 95th percentiles) control level with mean 55.9% (standard deviation = 15.1%) compared an value 63%. constructed SD rat provides foundation extrapolating human can be used future risk assessment.