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Title: Metabolism and physiologically based pharmacokinetic modeling of flumioxazin in pregnant animals

Abstract

A physiologically based pharmacokinetic (PBPK) model was developed to predict the concentration of flumioxazin, in the blood and fetus of pregnant humans during a theoretical accidental intake (1000 mg/kg). The data on flumioxazin concentration in pregnant rats (30 mg/kg po) was used to develop the PBPK model in pregnant rats using physiological parameters and chemical specific parameters. The rat PBPK model developed was extrapolated to a human model. Liver microsomes of female rats and a mixed gender of humans were used for the in vitro metabolism study. To determine the % of flumioxazin absorbed after administration at a dose of 1000 mg/kg assuming maximum accidental intake, the biliary excretion study of [phenyl-U-{sup 14}C]flumioxazin was conducted in bile duct-cannulated female rats (Crl:CD (SD)) to collect and analyze the bile, urine, feces, gastrointestinal tract, and residual carcass. The % of flumioxazin absorbed at a dose of 1000 mg/kg in rats was low (12.3%) by summing up {sup 14}C of the urine, bile, and residual carcass. The pregnant human model that was developed demonstrated that the maximum flumioxazin concentration in the blood and fetus of a pregnant human at a dose of 1000 mg/kg po was 0.86 μg/mL and 0.68 μg/mL, respectively, whichmore » is much lower than K{sub m} (202.4 μg/mL). Because the metabolism was not saturated and the absorption rate was low at a dose of 1000 mg/kg, the calculated flumioxazin concentration in pregnant humans was thought to be relatively low, considering the flumioxazin concentration in pregnant rats at a dose of 30 mg/kg. For the safety assessment of flumioxazin, these results would be useful for further in vitro toxicology experiments. - Highlights: • A PBPK model of flumioxazin in pregnant humans was developed. • Simulated flumioxazin concentration in pregnant humans was relatively low. • The results would be useful for further in vitro toxicology experiments.« less

Authors:
; ;
Publication Date:
OSTI Identifier:
22439735
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 277; Journal Issue: 3; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BILE; BILIARY TRACT; BLOOD; CARBON 14; CONCENTRATION RATIO; DOSES; EXCRETION; FECES; FETUSES; HUMAN POPULATIONS; IN VITRO; INTESTINES; LIVER; METABOLISM; MICROSOMES; PARTITION; RATS; RISK ASSESSMENT; UPTAKE; URINE

Citation Formats

Takaku, Tomoyuki, Nagahori, Hirohisa, and Sogame, Yoshihisa. Metabolism and physiologically based pharmacokinetic modeling of flumioxazin in pregnant animals. United States: N. p., 2014. Web. doi:10.1016/J.TAAP.2014.03.022.
Takaku, Tomoyuki, Nagahori, Hirohisa, & Sogame, Yoshihisa. Metabolism and physiologically based pharmacokinetic modeling of flumioxazin in pregnant animals. United States. https://doi.org/10.1016/J.TAAP.2014.03.022
Takaku, Tomoyuki, Nagahori, Hirohisa, and Sogame, Yoshihisa. 2014. "Metabolism and physiologically based pharmacokinetic modeling of flumioxazin in pregnant animals". United States. https://doi.org/10.1016/J.TAAP.2014.03.022.
@article{osti_22439735,
title = {Metabolism and physiologically based pharmacokinetic modeling of flumioxazin in pregnant animals},
author = {Takaku, Tomoyuki and Nagahori, Hirohisa and Sogame, Yoshihisa},
abstractNote = {A physiologically based pharmacokinetic (PBPK) model was developed to predict the concentration of flumioxazin, in the blood and fetus of pregnant humans during a theoretical accidental intake (1000 mg/kg). The data on flumioxazin concentration in pregnant rats (30 mg/kg po) was used to develop the PBPK model in pregnant rats using physiological parameters and chemical specific parameters. The rat PBPK model developed was extrapolated to a human model. Liver microsomes of female rats and a mixed gender of humans were used for the in vitro metabolism study. To determine the % of flumioxazin absorbed after administration at a dose of 1000 mg/kg assuming maximum accidental intake, the biliary excretion study of [phenyl-U-{sup 14}C]flumioxazin was conducted in bile duct-cannulated female rats (Crl:CD (SD)) to collect and analyze the bile, urine, feces, gastrointestinal tract, and residual carcass. The % of flumioxazin absorbed at a dose of 1000 mg/kg in rats was low (12.3%) by summing up {sup 14}C of the urine, bile, and residual carcass. The pregnant human model that was developed demonstrated that the maximum flumioxazin concentration in the blood and fetus of a pregnant human at a dose of 1000 mg/kg po was 0.86 μg/mL and 0.68 μg/mL, respectively, which is much lower than K{sub m} (202.4 μg/mL). Because the metabolism was not saturated and the absorption rate was low at a dose of 1000 mg/kg, the calculated flumioxazin concentration in pregnant humans was thought to be relatively low, considering the flumioxazin concentration in pregnant rats at a dose of 30 mg/kg. For the safety assessment of flumioxazin, these results would be useful for further in vitro toxicology experiments. - Highlights: • A PBPK model of flumioxazin in pregnant humans was developed. • Simulated flumioxazin concentration in pregnant humans was relatively low. • The results would be useful for further in vitro toxicology experiments.},
doi = {10.1016/J.TAAP.2014.03.022},
url = {https://www.osti.gov/biblio/22439735}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 3,
volume = 277,
place = {United States},
year = {Sun Jun 15 00:00:00 EDT 2014},
month = {Sun Jun 15 00:00:00 EDT 2014}
}