Metabolism and physiologically based pharmacokinetic modeling of flumioxazin in pregnant animals |
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Authors: | Tomoyuki Takaku Hirohisa NagahoriYoshihisa Sogame |
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Institution: | Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 1-98, 3-Chome, Kasugade-Naka, Konohana-Ku, Osaka 554-8558, Japan |
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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-14C]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 14C 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 Km (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. |
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Keywords: | PBPK physiologically based pharmacokinetics Km Michaelis&ndash Menten constant Vmax maximum velocity PPO protoporphyrinogen oxidase NMR nuclear magnetic resonance MS mass spectrometry PK pharmacokinetics LSC liquid scintillation counter Pt partition coefficient Ksi stomach-intestine transfer rate constant Kfe fecal excretion rate constant Ki intestinal uptake rate constant Fa fraction absorbed |
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