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Physiologically based pharmacokinetic model for chronic inhalation of 2-butoxyethanol.
- Source :
-
Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 1998 Dec; Vol. 153 (2), pp. 211-26. - Publication Year :
- 1998
-
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.<br /> (Copyright 1998 Academic Press.)
- Subjects :
- Administration, Inhalation
Age Factors
Animals
Binding Sites drug effects
Body Weight
Cardiac Output drug effects
Ethylene Glycols pharmacology
Female
Kidney physiology
Male
Mice
Protein Binding drug effects
Rats
Rats, Inbred F344
Sensitivity and Specificity
Sex Characteristics
Species Specificity
Time Factors
Ethylene Glycols pharmacokinetics
Models, Biological
Solvents pharmacokinetics
Solvents pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0041-008X
- Volume :
- 153
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Toxicology and applied pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 9878592
- Full Text :
- https://doi.org/10.1006/taap.1998.8518