A preliminary regional PBPK model of lung metabolism for improving species dependent descriptions of 1,3-butadiene and its metabolites

Abstract

1,3-Butadiene (BD), a volatile organic chemical (VOC), is used in synthetic rubber production and other industrial processes. It is detectable at low levels in ambient air as well as in tobacco smoke and gasoline vapors. Inhalation exposures to high concentrations of BD have been associated with lung cancer in both humans and experimental animals, although differences in species sensitivity have been observed. Metabolically active lung cells such as Pulmonary Type I and Type II epithelial cells and club cells (Clara cells)(1) are potential targets of BD metabolite-induced toxicity. Metabolic capacities of these cells, their regional densities, and distributions vary throughout the respiratory tract as well as between species and cell types. Here we present a physiologically based pharmacokinetic (PBPK) model for BD that includes a regional model of lung metabolism, based on a previous model for styrene, to provide species-dependent descriptions of BD metabolism in the mouse, rat, and human. Since there are no in vivo data on BD pharmacokinetics in the human, the rat and mouse models were parameterized to the extent possible on the basis of in vitro metabolic data. Where it was necessary to use in vivo data, extrapolation from rat to mouse was performed to evaluate the level of uncertainty in the human model. A kidney compartment and description of downstream metabolism were also included in the model to allow for eventual use of available urinary and blood biomarker data in animals and humans to calibrate the model for estimation of BD exposures and internal metabolite levels. Results from simulated inhalation exposures to BD indicate that incorporation of differential lung region metabolism is important in describing species differences in pulmonary response and that these differences may have implications for risk assessments of human exposures to BD.

Application of Minimal Physiologically-Based Pharmacokinetic Model to Simulate Lung and Trachea Exposure of Pyronaridine and Artesunate in Hamsters

“…The blood volume ( V blood ) and cardiac output ( Q co ) of hamsters that were reported in the literature were used for the PBPK model development [ 22 , 23 ]. The blood flow rate for the trachea ( Q trachea ) was calculated by multiplying Q co by 2.1% [ 24 , 25 , 26 ]. The blood flow rate for the rest of the body ( Q rest ) was calculated by subtracting Q trachea from Q co .…”

Advances in experimental and mechanistic computational models to understand pulmonary exposure to inhaled drugs

“…Some activities such as esterification of inhaled steroidal drugs are well-known examples of pulmonary metabolism (Miller-Larsson et al, 1998). In an interesting modelling approach for lung metabolism, Campbell et al (2015) developed a regional PBPK model for lung for 1,3-butadiene and its metabolites taking into account metabolic capabilities specific to sub-divided regions within lungs such as oral/nasal pathways, conducting airways (trachea, bronchi, and anterior bronchioles), transitional airways (terminal bronchioles), and the alveolar region. Results showed that inclusion of differential lung metabolism was important for explaining the observed species differences in the pulmonary metabolism of 1,3-butadiene.…”

Reactive Metabolites: Current and Emerging Risk and Hazard Assessments

“…Because of these difficulties, assessment of reactive metabolites is well suited to benefit from PBPK and PBPK/PD models which aim to describe the tissue exposure and potential toxicity of reactive metabolites in silico. Mathematical modeling for the predictive safety of reactive metabolites has been applied for years in the field of environmental toxicology, where such models allow studies to be simulated which would not be experimentally possible. , …”

“…Mathematical modeling for the predictive safety of reactive metabolites has been applied for years in the field of environmental toxicology, where such models allow studies to be simulated which would not be experimentally possible. 321,322 Understanding the propensity for a compound to induce damage through the production of reactive metabolites involves understanding the exposure of the parent in metabolic tissues, the rate of conversion to reactive metabolite, accumulation of the reactive metabolite, and the formation of adducts with endogenous proteins and neutralization processes (e.g., GSH) (Figure 10). The ADME of the parent can be modeled utilizing standard PBPK models, with emphasis on the distribution to the primary metabolic tissues (e.g., liver, kidney) and the rate of metabolic conversion into the reactive metabolite.…”