Format

Send to

Choose Destination
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.

Author information

1
ScitoVation, LLC, Research Triangle Park, North Carolina, USA.
2
Centre for Toxicology, University of Surrey, Surrey, United Kingdom.
3
The Hamner Institutes for Health Sciences, Research Triangle Park, NC, USA.
4
Duke medical center, Durham, NC, USA.
5
University of Georgia, Athens, GA, USA.
6
Science Strategies, LLC, Charlottesville, Virginia, USA.
7
Valent USA, LLC, Walnut Creek, California, USA.
8
Moire Creek Toxicology Consulting Services, Livermore, CA.
9
Syngenta, Greensboro, North Carolina, USA.
10
Ramboll, Research Triangle Park, North Carolina, USA.
11
ToxStrategies, Cary, North Carolina, USA.

Abstract

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.

KEYWORDS:

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

PMID:
30768128
DOI:
10.1093/toxsci/kfz042

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center