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Physiologically based pharmacokinetic modeling of deltamethrin: Development of a rat and human diffusion-limited model
Citation:
Godin, S. J., M. J. DEVITO, M. F. HUGHES, D. G. ROSS, J. M. STARR, R. W. SETZER, R. CONOLLY, R. TORNERO-VELEZ, AND E. J. Scollon. Physiologically based pharmacokinetic modeling of deltamethrin: Development of a rat and human diffusion-limited model. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 115(2):330-343, (2010).
Impact/Purpose:
A published PBPK model for deltamethrin in the rat was modified based on new data. The model predicts more accurately two published rat data sets and was scaled to humans.
Description:
Mirfazaelian et al. (2006) developed a physiologically based pharmacokinetic (PBPK) model for the pyrethroid pesticide deltamethrin in the rat. This model describes gastrointestinal tract absorption as a saturable process mediated by phase III efflux transporters which pump deltamethrin out of the intestinal enterocytes into the gastrointestinal tract lumen, resulting in minimal net absorption at low concentrations and increasing absorption at higher concentrations. In the present study, the dose-dependency in absorption of deltamethrin was examined in male Long Evans rats using oral exposures predicted by the Mirfazaelian model to yield different oral bioavailability values. No difference in the bioavailability from single oral doses of 0.3 and 3.0 mg deltamethrin/kg was observed. Based on this finding, the Mirfazaelian PBPK model was modified to exclude a saturable absorption process. Other changes to the Mirfazaelian model included describing all tissue compartments with diffusion-limited kinetics and a single blood compartment. These changes improved model predictions of deltamethrin tissue concentration data from the present study and the literature. The rat model was then scaled to humans. The model predicted a 2-fold greater peak deltamethrin brain concentration and 3-fold greater area under the curve (AUC(0-48h)) for humans following an oral exposure of 1 mg/kg. Based on this model, humans would have greater distribution of deltamethrin to the brain for the same administered oral dose compared to rats. The relative sensitivity to deltamethrin between rats and humans depend on both pharmacokinetic and pharmacodynamic differences. Species differences in the pharmacodynamic responses to deltamethrin between rats and humans remain uncharacterized.
