DEVELOPMENT OF A PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR DELTAMETHRIN in Adult and developing

Sprague-Dawley rats

Ahmad Mirfazaeliana, Kyu-Bong Kimb, Sathanandam S. Anandb, Hyo J. Kimb,
Rogelio Tornero-Velezc, James V. Brucknerb and Jeffrey W. Fishera

a: College of Public Health, Department of Environmental Health Science, University of Georgia, Athens, GA

b: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy,

University of Georgia, Athens, GA

c: U.S. Environmental Protection Agency, Office of Research and Development, National Exposure Research Laboratory, Research Triangle Park, NC

Deltamethrin (DLT) is a type II pyrethroid widely used in agriculture and public health. It is primarily cleared from the body by metabolism and biliary excretion. A physiologically based pharmacokinetic (PBPK) model for DLT was constructed for the adult (PND90) and developing (PND 10, 21, 40) male Sprague-Dawley rat. To develop the model, rats were administered 0.4-10 mg DLT/Kg in glycerol formal by gavage. Fat, brain and blood samples were collected at selected time-points after dosing. The toxicokinetics of DLT could not be described using flow-limited assumptions for all model compartments. We suspect that the lipophilicity of DLT precluded the use of flow-limited kinetics. A refined hybrid PBPK model for DLT was then developed using both flow-limited (spleen, GI tract, liver and rapidly perfused tissues) and diffusion-limited (brain, fat, blood and slowly perfused tissues) differential equations to describe the toxicokinetics of DLT. Metabolism of DLT was accounted for in blood and liver. Generalized Michaelis-Menten equations were used to calculate metabolic rate constants and organ weights of rats of different ages. The PBPK model predictions compared favorably with experimental blood, brain and fat DLT profiles over the range of doses. There was a linear negative correlation in the AUCs of plasma profiles from PND 10 to PND 40 and a moderate decline afterwards (up to PND 90). There was adequate agreement between model simulations and observations for most published time-course data. This research will advance the approaches used to construct PBPK models for highly lipophilic compounds such as pyrethroids. Although this work was reviewed by EPA and approved for publication, it may not necessarily reflect official Agency policy. (Supported by U.S.EPA STAR grant #R830800)