Physiologically based pharmacokinetic modeling of deltamethrin: development of a rat and human diffusion-limited model

Abstract

Mirfazaelian et al. developed a physiologically based pharmacokinetic (PBPK) model for the pyrethroid pesticide deltamethrin in the rat. This model describes gastrointestinal (GI) tract absorption as a saturable process mediated by phase III efflux transporters which pump deltamethrin out of the intestinal enterocytes into the GI 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 po exposures predicted by the Mirfazaelian model to yield different po bioavailability values. No difference in the bioavailability from single po doses of 0.3 and 3.0 mg/kg deltamethrin 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 twofold greater peak deltamethrin brain concentration and threefold greater area under the curve (AUC(0-48 h)) for humans following an po exposure of 1 mg/kg. Based on this model, humans would have greater distribution of deltamethrin to the brain for the same administered po dose compared to rats. The relative sensitivity to deltamethrin between rats and humans depends on both pharmacokinetic and pharmacodynamic differences. Species differences in the pharmacodynamic responses to deltamethrin between rats and humans remain uncharacterized.