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Development of a physiologically based pharmacokinetic model for methyl ethyl ketone in F344 rats.

Authors
Thrall-KD; Soelberg-JJ; Weitz-KK; Woodstock-AD
Source
J Toxicol Environ Health, A 2002 Jul; 65(13):881-896
NIOSHTIC No.
20029605
Abstract
A physiologically based pharmacokinetic (PBPK) model to describe the absorption, distribution, metabolism, and elimination of methyl ethyl ketone (MEK) in rats was developed. Partition coefficients were experimentally determined in rat tissues and blood samples using an in vitro vial equilibration technique. These solubility ratios were in agreement with previous human-based estimates that MEK is uniformly soluble within all tissues. The in vivo metabolism of MEK was evaluated using groups of three F344 male rats exposed to 100-2000 ppm MEK in a closed, recirculating gas uptake system. An optimal fit of a family of uptake curves was obtained by adjusting Michaelis-Menten metabolic constants, Km (affinity), and Vmax (capacity) using the PBPK model. At the highest chamber concentration, the uptake curve could not be modeled without the addition of a first-order (Kfo) metabolic pathway. Pretreatment with pyrazole, an inhibitor of oxidative microsomal metabolism, decreased the slope of the gas uptake curve but did not abolish metabolism. Optimal model fit to the gas uptake curve from pyrazole-pretreated animals required the apparent Km to be increased roughly 50 times the value determined in naive rats. The completed PBPK model was evaluated against real-time exhaled breath data collected from rats receiving an intravenous (iv) injection of MEK via a jugular vein cannula. Model simulation of the iv-treated animals required alveolar ventilation to be reduced 30% in order to match the data. Exhaled breath profiles from animals treated with MEK by oral gavage or intraperitoneal (ip) injection were evaluated and absorption rates was determined. Development of a comprehensive PBPK model for MEK in rats is the first step toward future extrapolations to apply to humans.
Keywords
Laboratory-animals; Animals; Animal-studies; Exposure-levels; Solvents; Breathing-atmospheres; Lung-function; Lung-tissue; Pulmonary-function; Pulmonary-system
Contact
Molecular Biosciences Department, Fundamental Science Division, Battelle, Pacific Northwest Laboratory, Richland, Washington 99352
CODEN
JTEHD6
CAS No.
1330-20-7; 13463-67-7; 108-88-3
Publication Date
20020712
Document Type
Journal Article
Email Address
karla.thrall@pnl.qov
Funding Amount
601586
Funding Type
Grant
Fiscal Year
2002
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-003658
Issue of Publication
13
ISSN
1528-7394
Priority Area
Disease and Injury: Allergic and Irritant Dermatitis
Source Name
Journal of Toxicology and Environmental Health, Part A: Current Issues
State
WA
Performing Organization
Battelle Memorial Institute, Richland, Washington
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