Physiologically based pharmacokinetic modeling of dibromoacetic acid in F344 rats

Journal Article · Thu Apr 15 00:00:00 EDT 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2009.12.033· OSTI ID:21344921

Matthews, Jessica L., E-mail: [e-mail] ^[1]; Schultz, Irvin R., E-mail: [e-mail] ^[2]; Easterling, Michael R., E-mail: [e-mail] ^[1]; Melnick, Ronald L., E-mail: [e-mail] ^[3]

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1. SRA International, Inc., 2605 Meridian Parkway, Suite 200, Durham, NC, 27713 (United States)
2. Battelle Pacific Northwest Laboratory, 1529 W. Sequim Bay Road, Sequim, WA, 98382 (United States)
3. Environmental Toxicology Program, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC, 27709 (United States)

A novel physiologically based pharmacokinetic (PBPK) model structure, which includes submodels for the common metabolites (glyoxylate (GXA) and oxalate (OXA)) that may be involved in the toxicity or carcinogenicity of dibromoacetic acid (DBA), has been developed. Particular attention is paid to the representation of hepatic metabolism, which is the primary elimination mechanism. DBA-induced suicide inhibition is modeled by irreversible covalent binding of the intermediate metabolite alpha-halocarboxymethylglutathione (alphaH1) to the glutathione-S-transferase zeta (GSTzeta) enzyme. We also present data illustrating the presence of a secondary non-GSTzeta metabolic pathway for DBA, but not dichloroacetic acid (DCA), that produces GXA. The model is calibrated with plasma and urine concentration data from DBA exposures in female F344 rats through intravenous (IV), oral gavage, and drinking water routes. Sensitivity analysis is performed to confirm identifiability of estimated parameters. Finally, model validation is performed with data sets not used during calibration. Given the structural similarity of dihaloacetates (DHAs), we hypothesize that the PBPK model presented here has the capacity to describe the kinetics of any member or mixture of members of this class in any species with the alteration of chemical-and species-specific parameters.

• OSTI ID: 21344921
• Journal Information: Toxicology and Applied Pharmacology, Vol. 244, Issue 2; Other Information: DOI: 10.1016/j.taap.2009.12.033; PII: S0041-008X(09)00540-7; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ACETIC ACID
BIOLOGICAL PATHWAYS
CALIBRATION
CHEMICAL BONDS
DRINKING WATER
GLUTATHIONE
KINETICS
LIVER
METABOLISM
METABOLITES
ORGANIC BROMINE COMPOUNDS
OXALATES
RATS
SENSITIVITY ANALYSIS
SIMULATION
TOXICITY
URINE
ANIMALS
BIOLOGICAL MATERIALS
BIOLOGICAL WASTES
BODY
BODY FLUIDS
CARBOXYLIC ACID SALTS
CARBOXYLIC ACIDS
DIGESTIVE SYSTEM
DRUGS
GLANDS
HYDROGEN COMPOUNDS
MAMMALS
MATERIALS
MONOCARBOXYLIC ACIDS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANS
OXYGEN COMPOUNDS
PEPTIDES
POLYPEPTIDES
PROTEINS
RADIOPROTECTIVE SUBSTANCES
RESPONSE MODIFYING FACTORS
RODENTS
VERTEBRATES
WASTES
WATER