ToxSci Advance Access originally published online on July 10, 2006
Toxicological Sciences 2006 93(2):432-442; doi:10.1093/toxsci/kfl056
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Development of a Physiologically Based Pharmacokinetic Model for Deltamethrin in the Adult Male Sprague-Dawley Rat
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* Department of Environmental Health Science, College of Public Health, University of Georgia, Athens, Georgia 30602-2102; Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602-2354; Pharmacology Department, National Institute of Toxicological Research, Korea Food and Drug Administration, Seoul 122-704, South Korea; and U.S. Environmental Protection Agency, Office of Research and Development, National Exposure Research Laboratory, Research Triangle Park, North Carolina 27709
Received February 20, 2006; accepted June 29, 2006
Deltamethrin (DLT) is a type II pyrethroid insecticide widely used in agriculture and public health. DLT is a potent neurotoxin that is primarily cleared from the body by metabolism. To better understand the dosimetry of DLT in the central nervous system, a physiologically based pharmacokinetic (PBPK) model for DLT was constructed for the adult, male Sprague-Dawley rat that employed both flow-limited (brain, gastrointestinal [GI] tract, liver, and rapidly perfused tissues) and diffusion-limited (fat, blood/plasma, and slowly perfused tissues) rate equations. The blood was divided into plasma and erythrocytes. Cytochrome P450–mediated metabolism was accounted for in the liver and carboxylesterase (CaE)-mediated metabolism in plasma and liver. Serial blood, brain, and fat samples were taken for DLT analysis for up to 48 h after adult rats received 2 or 10 mg DLT/kg po. Hepatic biotransformation accounted for 
78% of these administered doses. Plasma CaEs accounted for biotransformation of 8% of each dosage. Refined PBPK model forecasts compared favorably to the 2- and 10-mg/kg po blood, plasma, brain, and fat DLT profiles, as well as profiles subsequently obtained from adult rats given 1 mg/kg iv. DLT kinetic profiles extracted from published reports of oral and iv experiments were also used for verification of the model's simulations. There was generally good agreement in most instances between predicted and the limited amount of empirical data. It became clear from our modeling efforts that there is considerably more to be learned about processes that govern GI absorption and exsorption, transport, binding, brain uptake and egress, fat deposition, and systemic elimination of DLT and other pyrethroids. The current model can serve as a foundation for construction of models for other pyrethroids and can be improved as more definitive information on DLT kinetic processes becomes available.
Key Words: deltamethrin; PBPK modeling; male Sprague-Dawley rat; pyrethroids; toxicokinetics.
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