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Physiologically based pharmacokinetic model for chronic inhalation of 2-butoxyethanol.
Toxicol Appl Pharmacol. 1998 Dec; 153(2):211-26.TA

Abstract

2-Butoxyethanol (2BE) is used extensively in the production of cleaning agents and as a general solvent. It is primarily metabolized in the liver to 2-butoxyacetic acid (2BAA), which is excreted in urine. The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model describing the toxicokinetic behavior of 2BE and 2BAA in different species following repeated, long-term exposures. The PBPK model was first developed for short-term 2BE exposure to male rats. Allometric scaling was employed to estimate physiological and biochemical model parameters based on body weight. To accommodate differences in 2BE toxicokinetics in female rats, a higher Vmax for 2BE metabolism to 2BAA, higher plasma protein binding sites for 2BAA, and lower Vmax for 2BAA excretion through the kidney were incorporated into the model. For mice, a higher Vmax for 2BE metabolism to 2BAA for both sexes and higher plasma protein binding sites for 2BAA for female mice were also incorporated into the model. Subsequently, the model was expanded to simulate 2BE and 2BAA toxicokinetics for long-term, repeated exposures by incorporating time-dependent changes in model parameters. To reflect physiological/biochemical changes in animals during a chronic exposure, parameters for cardiac output, body composition, metabolic capacity, protein binding, or capacity of renal excretion were adjusted over time depending on species and sex. Sensitivity analysis was performed to better understand how sensitive model responses were to uncertainties in input parameters. The resulting PBPK model was used to simulate toxicokinetic data acquired during a 2-year inhalation toxicity and carcinogenicity study in male and female F344/N rats and B6C3F1 mice.

Authors+Show Affiliations

Preclinical Drug Development-Northwest Operations, Battelle, Richland, Washington, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9878592

Citation

Lee, K M., et al. "Physiologically Based Pharmacokinetic Model for Chronic Inhalation of 2-butoxyethanol." Toxicology and Applied Pharmacology, vol. 153, no. 2, 1998, pp. 211-26.
Lee KM, Dill JA, Chou BJ, et al. Physiologically based pharmacokinetic model for chronic inhalation of 2-butoxyethanol. Toxicol Appl Pharmacol. 1998;153(2):211-26.
Lee, K. M., Dill, J. A., Chou, B. J., & Roycroft, J. H. (1998). Physiologically based pharmacokinetic model for chronic inhalation of 2-butoxyethanol. Toxicology and Applied Pharmacology, 153(2), 211-26.
Lee KM, et al. Physiologically Based Pharmacokinetic Model for Chronic Inhalation of 2-butoxyethanol. Toxicol Appl Pharmacol. 1998;153(2):211-26. PubMed PMID: 9878592.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Physiologically based pharmacokinetic model for chronic inhalation of 2-butoxyethanol. AU - Lee,K M, AU - Dill,J A, AU - Chou,B J, AU - Roycroft,J H, PY - 1999/1/8/pubmed PY - 1999/1/8/medline PY - 1999/1/8/entrez SP - 211 EP - 26 JF - Toxicology and applied pharmacology JO - Toxicol Appl Pharmacol VL - 153 IS - 2 N2 - 2-Butoxyethanol (2BE) is used extensively in the production of cleaning agents and as a general solvent. It is primarily metabolized in the liver to 2-butoxyacetic acid (2BAA), which is excreted in urine. The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model describing the toxicokinetic behavior of 2BE and 2BAA in different species following repeated, long-term exposures. The PBPK model was first developed for short-term 2BE exposure to male rats. Allometric scaling was employed to estimate physiological and biochemical model parameters based on body weight. To accommodate differences in 2BE toxicokinetics in female rats, a higher Vmax for 2BE metabolism to 2BAA, higher plasma protein binding sites for 2BAA, and lower Vmax for 2BAA excretion through the kidney were incorporated into the model. For mice, a higher Vmax for 2BE metabolism to 2BAA for both sexes and higher plasma protein binding sites for 2BAA for female mice were also incorporated into the model. Subsequently, the model was expanded to simulate 2BE and 2BAA toxicokinetics for long-term, repeated exposures by incorporating time-dependent changes in model parameters. To reflect physiological/biochemical changes in animals during a chronic exposure, parameters for cardiac output, body composition, metabolic capacity, protein binding, or capacity of renal excretion were adjusted over time depending on species and sex. Sensitivity analysis was performed to better understand how sensitive model responses were to uncertainties in input parameters. The resulting PBPK model was used to simulate toxicokinetic data acquired during a 2-year inhalation toxicity and carcinogenicity study in male and female F344/N rats and B6C3F1 mice. SN - 0041-008X UR - https://www.unboundmedicine.com/medline/citation/9878592/Physiologically_based_pharmacokinetic_model_for_chronic_inhalation_of_2_butoxyethanol_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(98)98518-0 DB - PRIME DP - Unbound Medicine ER -