Use of a Hybrid Computational Fluid Dynamics and Physiologically Based Inhalation Model for Interspecies Dosimetry Comparisons of Ester Vapors

Frederick, Clay B.; Lomax, Larry G.; Black, Kurt A.; Finch, Lavorgie; Scribner, H. E.; Kimbell, Julia S.; Morgan, Kevin T.; Subramaniam, Ravi P.; Morris, John B.

doi:10.1006/taap.2002.9451

Cited by 51 publications

(25 citation statements)

References 57 publications

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“…The size of the particles inhaled will dictate how far into the respiratory tract the particles will travel and where the interaction between particle and tissue surface may occur (Conolly et al, 2000(Conolly et al, , 2002(Conolly et al, , 2004Hofmann et al, 2000;Asgharian, 2001;Kelly et al, 2001 a and b;Overton et al, 2001;Cassee et al, 2002;Frederick et al, 2002;Georgieva et al, 2003;Asgharian et al, 2004Asgharian et al, , 2006Asgharian et al, , 2011Asgharian and Price, 2006;Schroeter et al, 2006;Carey et al, 2007;Kimbell et al, 2007;Asgharian et al, 2012 a and b;Schroeter et al, 2012).…”

Section: Structure and Function Of Normal Respiratory Defensesmentioning

confidence: 96%

The Effect of Particle Deposition on Immunological Response as Measured by Cytokine Production

Singal¹

2015

Comparative Biology of the Normal Lung

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Section: Structure and Function Of Normal Respiratory Defensesmentioning

confidence: 96%

The Effect of Particle Deposition on Immunological Response as Measured by Cytokine Production

Singal¹

2015

Comparative Biology of the Normal Lung

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“…Computational modeling of physical phenomena can be leveraged to accurately describe exposure. For example, computational fluid dynamics-based description of compound deposition in the respiratory tract (Frederick et al, 2002) yields improved accuracy in the description of absorption for toxico-pharmacokinetic models (Campbell et al, 2014).…”

Section: Roadmap For the Futurementioning

confidence: 99%

Systems biology for organotypic cell cultures

Grego

Dougherty

Alexander

et al. 2017

ALTEX

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“…circulation of di-n-butylphthalate to the monobutylphthalate and the glucuronide; compounds that cause impairment of male reproductive tissues (Clewell et al, 2008); the metabolism and oral absorption and of atrazine on toxicity of the pituitary axis and enzyme inhibition (McMullin et al, 2007); the metabolism-associated toxicities of trichloroethylenes (Dobrev et al, 2002); the bioactivation of vinyl chloride to the DNA-reactive epoxide (Reitz et al, 1996;Clewell et al, 2001); and the inhalation toxicity of acrylate ester (Frederick et al, 1998(Frederick et al, , 2002Sweeney et al, 2004). The in vitro/in vivo drug and metabolite transport/distribution and elimination behavior, especially in target organs, should be studied to add to the robustness of the PBPK model.…”

Section: Metabolite Kinetics In Intestinementioning

confidence: 99%

Disparity in Intestine Disposition between Formed and Preformed Metabolites and Implications: A Theoretical Study

Sun

Pang²

2008

Drug Metab Dispos

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ABSTRACT:Metabolite in safety testing has been proposed for toxicity assessments. The question of how exposure of the synthetic metabolite compared with that of the formed metabolite was appraised kinetically by using physiologically based pharmacokinetic models, the (traditional) physiological model (TM), and segregated flow (SFM) models. The SFM differs from the TM and describes a partial (ϳ10% total) intestinal flow that perfuses the absorptive, metabolic, and secretory enterocyte layer to account for the higher extent of metabolism observed with oral versus systemic dosing of drugs. Theoretical solutions for the areas under the curve (AUC) of the formed metabolite after oral and intravenous administration of the precursor (AUC{mi,P}) and preformed, synthetic metabolite (AUC{pmi}) showed identical AUC iv {mi,P}, AUC po {mi,P}, and AUC po {pmi} for both the TM and SFM, whereas a larger AUC iv {pmi} existed for the SFM. The AUC{pmi} was influenced by metabolite parameters only: binding, absorptive (k a {mi}) and luminal degradation (k g {mi}) constants, intrinsic clearances for metabolism (CL int,met,I {mi}), apical efflux (CL int,sec,I {mi}), and basolateral transfer (CL d1 {mi} and CL d2 {mi}) for the metabolite. By contrast, the AUC{mi,P} was influenced additionally by precursor parameters: rate constants k a and k g , and CL int,met,I and CL int,sec,I , but not the basolateral transfer clearances. The drug parameters: CL int,met,I and k a increased whereas CL int,sec,I decreased AUC{mi,P}, and the effect of secretion was counterbalanced by reabsorption with high k a values. The simulated time courses for the metabolites and the AUC{pmi} and AUC{mi,P} resulting from intravenous and oral routes of administration of preformed metabolite and precursor differed, inferring that the kinetics of the preformed and formed metabolites are not identical.Metabolite-in-safety testing and the attainment of safe and efficacious drug use are key concerns in the drug development/surveillance paradigm. There has been a resurgence of interest in the testing of metabolites that are mediators of drug activity and toxicity due to the improvement in analytical methods for their detection, isolation, and characterization (Baillie et al., 2002). Metabolite testing is recommended, especially when metabolites are unique and identified only in humans, or when the metabolite exists at disproportionately higher levels in humans (Ͼ10%) than the animal species that was used for standard, nonclinical toxicology testing (Naito et al., 2007) (February, 2008 FDA Guidance for Industry, Safety Testing of Drug Metabolites. Pharmacology and Toxicology; http://www.fda.gov/cder/guidance/). It has been proposed that a metabolite is considered to be a major metabolite when the metabolite represents Ͼ10% (Davis-Bruno and Atrakchi, 2006) or 25% exposure (or area under the curve) of the precursor (Baillie et al., 2002). Others have suggested the estimate to be based on unbound concentration in the circulation or amounts in the excreta (Smith and Obach...

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Use of a Hybrid Computational Fluid Dynamics and Physiologically Based Inhalation Model for Interspecies Dosimetry Comparisons of Ester Vapors

Cited by 51 publications

References 57 publications

The Effect of Particle Deposition on Immunological Response as Measured by Cytokine Production

The Effect of Particle Deposition on Immunological Response as Measured by Cytokine Production

Systems biology for organotypic cell cultures

Disparity in Intestine Disposition between Formed and Preformed Metabolites and Implications: A Theoretical Study

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