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Toxicol Sci. 2019 Feb 15. pii: kfz042. doi: 10.1093/toxsci/kfz042. [Epub ahead of print]

Evaluation of Age-related Pyrethroid Pharmacokinetic Differences in Rats: Physiologically-based Pharmacokinetic Model Development using In Vitro Data and In Vitro to In Vivo Extrapolation.

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ScitoVation, LLC, Research Triangle Park, North Carolina, USA.
Centre for Toxicology, University of Surrey, Surrey, United Kingdom.
The Hamner Institutes for Health Sciences, Research Triangle Park, NC, USA.
Duke medical center, Durham, NC, USA.
University of Georgia, Athens, GA, USA.
Science Strategies, LLC, Charlottesville, Virginia, USA.
Valent USA, LLC, Walnut Creek, California, USA.
Moire Creek Toxicology Consulting Services, Livermore, CA.
Syngenta, Greensboro, North Carolina, USA.
Ramboll, Research Triangle Park, North Carolina, USA.
ToxStrategies, Cary, North Carolina, USA.


An in vitro to in vivo (IVIVE) extrapolation based-physiologically based pharmacokinetic (PBPK) modeling approach was demonstrated to understand age-related differences in kinetics and how they potentially affect age-related differences in acute neurotoxic effects of pyrethroids. To describe the age-dependent changes in pyrethroid kinetics, it was critical to incorporate age-dependent changes in metabolism into the model. As such, in vitro metabolism data were collected for three selected pyrethroids, deltamethrin, cis-permethrin, and trans-permethrin, using liver microsomes and cytosol, and plasma prepared from immature and adult rats. Resulting metabolism parameters, maximum rate of metabolism (Vmax) and Michaelis-Menten constant (Km), were biologically scaled to respective in vivo parameters for use in the age-specific PBPK model. Then, age-dependent changes in target tissue exposure, i.e., brain Cmax, to a given pyrethroid were simulated across ages using the model. The PBPK model recapitulated in vivo time-course plasma and brain concentrations of the three pyrethroids in immature and adult rats following oral administration of both low and high doses of these compounds. A single model structure developed for DLM was able to describe the kinetics of the other two pyrethroids when used with compound-specific and age-specific metabolism parameters, suggesting that one generic model for pyrethroids as a group can be used for early age-sensitivity evaluation if appropriate metabolic parameters are used. The current study demonstrated the validity of applying IVIVE-based PBPK modeling to development of age-specific PBPK models for pyrethroids in support of pyrethroid risk assessment of potentially-sensitive early age populations in humans.


In vitro to in vivo extrapolation; Metabolism; PBPK model; Pyrethroids; Risk Assessment


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