Metabolism and physiologically based pharmacokinetic modeling of flumioxazin in pregnant animals.
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 (1000mg/kg). The data on flumioxazin concentration in pregnant rats (30mg/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 1000mg/kg assuming maximum accidental intake, the biliary excretion study of [phenyl-U-(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 1000mg/kg in rats was low (12.3%) by summing up (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 1000mg/kg po was 0.86μg/mL and 0.68μg/mL, respectively, which is much lower than Km (202.4μg/mL). Because the metabolism was not saturated and the absorption rate was low at a dose of 1000mg/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 30mg/kg. For the safety assessment of flumioxazin, these results would be useful for further in vitro toxicology experiments.
Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 1-98, 3-Chome, Kasugade-Naka, Konohana-Ku, Osaka 554-8558, Japan. Electronic address: takakut@sc.sumitomo-chem.co.jp.
Tomoyuki
T
Takaku
Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 1-98, 3-Chome, Kasugade-Naka, Konohana-Ku, Osaka 554-8558, Japan.
Hirohisa
H
Nagahori
Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 1-98, 3-Chome, Kasugade-Naka, Konohana-Ku, Osaka 554-8558, Japan.
Yoshihisa
Y
Sogame
D000818:Animals; D048588:Benzoxazines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D006540:Herbicides / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D015394:Molecular Structure; D010797:Phthalimides / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D048588:Benzoxazines; D006540:Herbicides; D010797:Phthalimides; C106487:flumioxazin
Herbicide; Metabolism; PBPK; Pregnant human