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.

Effects of Developmental Deltamethrin Exposure on White Adipose Tissue Gene Expression

“…There have been no comparative studies in rodent and humans to determine half-lives of the parent compound, but separate studies have presented the halflife of deltmethrin, in humans and rats, to appear to be in a similar range of several hours. It should be noted that recent pharmacokinetic modeling in rats predicted that humans would experience a higher brain concentration of deltamethrin compared to rodents, most likely because humans do not have plasma carboxylesterase activity [20].…”

Parameters for Pyrethroid Insecticide QSAR and PBPK/PD Models for Human Risk Assessment

“…1F, Appendix F. Preliminary ACSL-based physiological models were also written for deltamethrin, cis/trans permethrin, and cis/trans resmethrin (Knaak, unpublished). A PBPK model was developed for deltamethrin (Mirfazaelian et al 2006;Godin et al 2010;Tornero-Velez et al 2010) to assess internal dose levels in various organs and tissues of rats and humans. Deltamethrin was selected to represent the disposition of the pyrethroids, because it is structurally similar to other commercial (14), involving ACD Log D pH 7.4, was used to calculate the partition coefficients for liver.…”

“…An important characteristic of these models is that they incorporate diffusionlimited kinetics. Godin et al (2010) proposed diffusion-limited kinetics in all tissues, while Mirfazaelian et al (2006) and Tornero-Velez et al (2010) proposed mixed-flow and diffusion-limited kinetics. Based on a finding of apparent firstorder kinetic behavior, Godin et al (2010) applied a first-order clearance structure in modeling the biotransformation of deltamethrin.…”

Pyrethroids and Their Effects on Ion Channels

“…Clearance from plasma is relatively fast as pyrethroids are distributed throughout the body [27], with plasma half lives (t½) of the pyrethroid class ranging from 9-15 hours (hrs) [28]. In animal models pyrethroids exhibit peak concentration in the brain within 2-3 hrs after oral administration and decrease rapidly [27,29]. Brain pyrethroid levels are relatively low (0.1-0.3% of body burden), even at the time of peak symptom expression [28].…”