Metabolism of 2,6-dichloro-4-(3,3-dichloroallyloxy)phenyl 3-[5-(trifluoromethyl)-2-pyridyloxy]propyl ether (pyridalyl) in rats after repeated oral administration and a simple physiologically based pharmacokinetic modeling in brown and white adipose tissues.

Male and female Sprague-Dawley rats received repeated oral administration of 14C-2,6-dichloro-4-(3,3-dichloroallyloxy)phenyl 3- [5-(trifluoromethyl)-2-pyridyloxy]propyl ether (14C-pyridalyl) at 5 mg/kg/day for 14 consecutive days, and 14C excretion, 14C concentration in tissues, and the metabolic fate were determined. Most 14C was excreted into feces. The 14C concentrations in the blood and tissues attained steady-state levels at days 6 to 10, whereas those in white adipose tissues increased until day 14. Tissue 14C concentrations were highest in brown and white adipose tissue (38.37-57.50 ppm) but were 5.60 ppm or less in all the other tissues. Total 14C residues in blood and tissues on the 27th day after the first administration accounted for 2.6 to 3.2% of the total dose. A major fecal metabolite resulted from O-dealkylation. Analysis of metabolites in tissues revealed that the majority of 14C in perirenal adipose tissue and lungs was pyridalyl, accounting for greater than 90 and 60%, respectively, of the total, whereas a major metabolite in whole blood, kidneys, and liver was a dehalogenated metabolite. The experimental data were simulated with simple physiologically based pharmacokinetics using four-compartment models with assumption of lymphatic absorption and membrane permeability in adipose tissues. The different kinetics in brown and white adipose tissues was reasonably predicted in this model, with large distribution volume in adipose tissues and high hepatic clearance in liver. Sex-related difference of pyridalyl concentration in liver was considered to be a result of different unbound fraction times the hepatic intrinsic clearance (f x CL(int)) of 1.8 and 12 l/h for male and female, respectively.

Highly sensitive reporter gene assay for dioxins in human plasma by using cycloheximide as an enhancer substance.

A reporter gene assay (RGA) that uses a mouse liver recombinant Hepa1c1c7 containing the firefly luciferase gene was developed to screen for dioxins in human plasma. For a high-sensitivity method, the addition of cycloheximide to the culture medium brought about a fivefold increase in the sensitivity. The detection limit was 0.1 pg/microL/well. Aryl hydrocarbon receptor (AhR) binding affinity factors (AhR-BAF), calculated from the effect concentration 50 (EC(50)) value, showed approximately the same values as those in WHO-TEF (2006). A significant correlation between RGA and the conventional gas chromatography/mass spectrometry (GC/MS) method was obtained.

Metabolism of flufenpyr-ethyl in rats and mice.

The metabolism of flufenpyr-ethyl [ethyl 2-chloro-5-[1,6-dihydro-5-methyl-6-oxo-4-(trifluoromethyl)pyridazin-1-yl]-4-fluorophenoxyacetate] was examined in rats and mice. [Phenyl-(14)C]flufenpyr-ethyl was administered to rats and mice as a single oral dose at a level of 500 mg/kg, and (14)C-excretion was examined. Total (14)C-recoveries within 7 days after administration were 93.2 to 97.5% (feces, 42.0 to 46.0%; and urine, 47.2 to 55.5%) in rats and 92.6 to 96.4% (feces, 26.7 to 32.7%; and urine, 59.9 to 69.7%) in mice. (14)C-Excretion into expired air was not detected in rats (expired air of mice was not analyzed). No marked species- or sex-related differences were observed in the rate of (14)C-elimination, but a relatively higher excretion into the urine of mice was observed compared to that in rats. (14)C-residues in tissue 7 days after administration were relatively high for liver, hair, skin, and kidney, but total (14)C-residues were low, below 0.2% of the dose. An ester cleaved metabolite (S-3153acid) was the major metabolite in feces and urine. Hydroxylation of the methyl group on the C5 of the pyridazine ring and ether cleavage were also observed. No sex-related differences were observed in (14)C-elimination, (14)C-distribution, and metabolite profiles, and metabolism of flufenpyr-ethyl in rats and mice was similar. In vitro metabolism of flufenpyr-ethyl was examined using stomach and intestinal contents and blood and liver S9 fractions (postmitochondrial supernatant fractions) in rats. S-3153acid was detected as a major metabolite in the presence of intestinal contents and blood and liver S9 fractions, and a small amount was also formed in the presence of stomach contents, indicating that the parent compound is rapidly metabolized by intestinal contents and blood and liver S9 fractions through ester cleavage.