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Physiologically based pharmacokinetics of 2-butoxyethanol and its major metabolite, 2-butoxyacetic acid, in rats and humans.
- Source :
-
Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 1994 Nov; Vol. 129 (1), pp. 61-79. - Publication Year :
- 1994
-
Abstract
- A physiologically based pharmacokinetic model was developed to describe the disposition of 2-butoxyethanol (CAS 111-76-2) and its major metabolite, 2-butoxyacetic acid, in rats and humans. A previous human inhalation model by Johanson (Toxicol. Lett. 34, 23 (1986)) was expanded to include additional routes of exposure, physiological descriptions for rats, competing pathways for metabolism of 2-butoxyethanol, and measured partition coefficients for 2-butoxyethanol and 2-butoxyacetic acid. Simulations were compared to data gathered from rats following either intravenous infusion or oral or inhalation exposure and from humans following either inhalation or dermal exposure to 2-butoxyethanol. It was necessary to add equations for both protein binding of 2-butoxyacetic acid in blood and saturable elimination of 2-butoxyacetic acid by the kidneys to consistently describe the data. While the model predicted that rats metabolize 2-butoxyethanol and eliminate the acid metabolite faster per kilogram body weight than humans, the balance of these two processes in addition to physiological differences between species resulted in higher predicted peak blood concentrations as well as total areas under the blood concentration time curves for 2-butoxyacetic acid for rats versus humans. These species differences in kinetics coupled with the fact that human blood is significantly less susceptible than rat blood to the hemolytic effects of 2-butoxyacetic acid indicate that there is considerably less risk for hemolysis in humans as a result of exposure to 2-butoxyethanol than would have been predicted solely from standard toxicity studies with rats.
- Subjects :
- Administration, Cutaneous
Administration, Inhalation
Administration, Oral
Animals
Body Weight drug effects
Body Weight physiology
Computer Simulation
Ethylene Glycols administration & dosage
Ethylene Glycols blood
Ethylene Glycols urine
Glycolates administration & dosage
Glycolates blood
Glycolates urine
Hemolysis drug effects
Humans
Infusions, Intravenous
Kidney metabolism
Liver metabolism
Male
Models, Biological
Rats
Rats, Inbred F344
Solubility
Species Specificity
Tissue Distribution physiology
Ethylene Glycols pharmacokinetics
Glycolates pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 0041-008X
- Volume :
- 129
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Toxicology and applied pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 7974497
- Full Text :
- https://doi.org/10.1006/taap.1994.1229