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PBPK Model for Atrazine and Its Chlorotriazine Metabolites in Rat and Human.
- Source :
-
Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2016 Apr; Vol. 150 (2), pp. 441-53. Date of Electronic Publication: 2016 Jan 21. - Publication Year :
- 2016
-
Abstract
- The previously-published physiologically based pharmacokinetic model for atrazine (ATZ), deisopropylatrazine (DIA), deethylatrazine (DEA), and diaminochlorotriazine (DACT), which collectively comprise the total chlorotriazines (TCT) as represented in this study, was modified to allow for scaling to humans. Changes included replacing the fixed dose-dependent oral uptake rates with a method that represented delayed absorption observed in rats administered ATZ as a bolus dose suspended in a methylcellulose vehicle. Rate constants for metabolism of ATZ to DIA and DEA, followed by metabolism of DIA and DEA to DACT were predicted using a compartmental model describing the metabolism of the chlorotriazines by rat and human hepatocytesin vitro Overall, the model successfully predicted both the 4-day plasma time-course data in rats administered ATZ by bolus dose (3, 10, and 50 mg/kg/day) or in the diet (30, 100, or 500 ppm). Simulated continuous daily exposure of a 55-kg adult female to ATZ at a dose of 1.0 µg/kg/day resulted in steady-state urinary concentrations of 0.6, 1.4, 2.5, and 6.0 µg/L for DEA, DIA, DACT, and TCT, respectively. The TCT (ATZ + DEA + DIA + DACT) human urinary biomonitoring equivalent concentration following continuous exposure to ATZ at the chronic point of departure (POD = 1.8 mg/kg/day) was 360.6 μg/L.<br /> (© The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology.)
- Subjects :
- Absorption, Physiological
Administration, Oral
Animals
Atrazine blood
Atrazine urine
Cells, Cultured
Dose-Response Relationship, Drug
Female
Hepatocytes drug effects
Humans
Rats, Sprague-Dawley
Species Specificity
Tissue Distribution
Triazines blood
Triazines urine
Atrazine pharmacokinetics
Hepatocytes metabolism
Models, Biological
Triazines pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1096-0929
- Volume :
- 150
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Toxicological sciences : an official journal of the Society of Toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 26794140
- Full Text :
- https://doi.org/10.1093/toxsci/kfw014