Absorption, Distribution and Excretion
Jugular vein cannulated rats (n=5 males and n=5 females per group) were sacrificed 48 hours after administration. Bile duct cannulated rats (n=3 males per group) were sacrificed 24 hours after administration. Blood samples were collected from the jugular vein cannulation site at 0.25, 0.5, 0.75, 1, 1.5, 3, 6, 12, 24, and 48 hours after administration. Urine, feces, and bile were collected periodically throughout the study. At a dose of 10 mg/kg body weight, peak plasma radioactivity (Cmax) occurred approximately 0.5 hours after administration (2–3 μg equivalents/g); at a dose of 500 mg/kg body weight, peak plasma radioactivity (Cmax) occurred approximately 1.5 hours after administration (80–90 mg equivalents/g). There were no significant differences between the repeated-dose and single-dose groups. The clearance patterns of radioactive substances in the blood were similar. Following a single radiolabeled dose, a single radiolabeled dose after repeated administration, and treatment with 500 mg/kg body weight (14C-quinoxaline), the area under the plasma concentration-time curve (AUC) for radiolabel clearance in males was 22.3, 27.3, and 922 μg equivalents·hr/g, respectively, and in females it was 30.4, 29.6, and 963 μg equivalents·hr/g, respectively. 24 hours after administration, 68–85% of the administered radioactive material was recovered from feces and urine, indicating rapid clearance from the body. 48 hours later, 90–96% of the administered dose (14C-quinoline ring-labeled quinoxaline) was recovered in urine, feces, cage cleaning fluid, and tissues. Feces were the primary route of clearance, with 68–78% of the administered dose excreted in feces within 48 hours, and 13–20% in urine. The urinary half-life was 6–10 hours. The radiolabeled dose accounted for 1-7% in tissues and carcasses, <3% in gastrointestinal contents, and <1% in final cage cleaning solution. There was no gender difference in the distribution of radiolabeled dose. Repeated administration of quinoline ring-labeled quinoline 48 hours after a single administration of 10 mg/kg body weight, the distribution of radiolabeled dose (per gram of administered dose per tissue) in various organs and tissues showed the highest levels in perirenal fat (male 0.12, female 0.35) > ovary (0.07) > liver (male 0.027, female 0.045) and kidney (male 0.014, female 0.033). Significant levels of radiolabeled dose were also detected in the skin. After repeated administration, the levels of radiolabeled dose were similar; similar distribution patterns were also observed after administration of a higher dose of 500 mg/kg body weight. Tissue concentration data close to the plasma Cmax time point are lacking. Comparison of relative concentrations in bile and urine of intact and bile-cannulated rats showed that a 10 mg/kg body weight dose of quinoline induced extensive enterohepatic circulation. In bile-cannulated rats, the fecal radiolabeled content of the 10 mg/kg body weight dose group (14.3%) was significantly different from that of the 500 mg/kg body weight dose group (57.3%); the bile radiolabeled content of the 10 mg/kg body weight dose group (54.4%) was also significantly different from that of the 500 mg/kg body weight dose group (21.4%). These results indicate that the absorption of quinoline at a dose of 500 mg/kg body weight is saturated. For more complete data on the absorption, distribution, and excretion of quinoline (7 in total), please visit the HSDB records page.

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Metabolism/Metabolites
Five Fischer 344 rats (half male and half female) were given a single oral dose of 10 or 500 mg/kg of quinoline ring-labeled (14)C-quinoxaline (XDE-795, radiochemical purity >99%, specific activity 28.5 mCi/mmol), or 10 mg/kg of non-radioactively labeled quinoxaline (XDE-795, purity 99%) orally for 14 consecutive days, followed by a single oral dose of 10 mg/kg of (14)C-quinoxaline. Three male bile duct cannulated rats received a single injection of 10 or 500 mg/kg of quinoline ring-labeled (14)C-quinoxaline, and were sacrificed 24 hours later. One rat from each sex in each group received an injection of 10 mg/kg of benzene-labeled (radiochemical purity 98.5%, specific activity 27.8 mCi/mmol) or quinoline-labeled (14)C-quinoxaline for metabolite analysis. The major metabolites identified in urine originated from the cleavage of the quinoxaline diarylether bond, generating acid-labile 4-fluorophenol (4-FP) and 5,7-dichloro-4-hydroxyquinoline (DCHQ) conjugates, as well as small amounts of free DCHQ and 4-FP. Glucuronide and/or sulfate conjugates of the two fluorobenzene ring hydroxyquinoline isomers were detected in bile. Parental quinoline and free forms of the same two fluorobenzene ring hydroxyquinoline isomers as in bile were also detected in feces. There were no substantial differences in the metabolism and distribution of quinoline between sexes or between single and repeated administrations.
In a preliminary study of rats administered benzene-labeled 14C-quinoline, HPLC separation of 0-12 hour urine samples yielded eight peaks, designated P1-P7 and P10. Peak P5 was the major urinary component in the unhydrolyzed urine sample (80% in males and 77.4% in females), followed by P3 (7.9% and 9.5%, respectively), P1 (4.2% and 4.7%, respectively), and P6 (3.1% and 3.0%, respectively). The remaining peaks contained less than 3% of the radiolabeled urinary marker. After acid hydrolysis of the urine, the HPLC chromatogram changed significantly. The major component in the unhydrolyzed urine decreased to only 2.4% of the total urine volume; instead, P8 (not detected in the unhydrolyzed sample) became the major component (73.6%). This suggests that P5 may be a conjugate of P8. Component P8 was co-eluted with 4-fluorophenol standard. The minor peaks remaining after acid hydrolysis were P3 (11.7%), P9 (7.1%), and P1 (5.2%), but these metabolites were not identified. The standards used were 4-fluorophenol, 2-hydroxyquinoline, and the parent quinoline. The retention times of the parent quinoline and 2-hydroxyquinoline did not match the retention times of any of the HPLC urine components. The fecal metabolites of phenyl-(14)-quinoxaline showed a similar pattern to those of quinoline-(14)-quinoxaline. High-performance liquid chromatography (HPLC) separation of mixed urine samples from rats treated with quinoline-(14)-quinoxaline revealed up to 16 radiolabeled peaks, named Q1-Q16, before and after acid hydrolysis. In male rats receiving a single dose of 10 mg/kg body weight, eight peaks were identified in unhydrolyzed urine: Q3, Q4, Q7, Q8, Q9, Q11, Q12, and Q13. In female rats receiving a single dose of 10 mg/kg body weight, four additional peaks were detected: Q2, Q5, Q10, and Q15 (detected only in the repeat-dose group). At a dose of 500 mg/kg body weight, the peak values appearing in the radiochromatograms of mixed urine samples from male and female mice at 0–12 hours were Q7, Q8, Q9, Q10 (female only), Q11, Q12, and Q13, respectively. The major peaks were Q11 (13–33%), Q8 (13–24%), Q9 (9–24%), Q12 (10–18%), Q13 (6–15%), Q7 (4–11%), and Q4 (<13%), respectively. The only definitively identified urinary metabolite was 5,7-dichloro-4-hydroxyquinoline (DCHQ), which co-eluted with peak Q13. Acid hydrolysis resulted in a 2-4 fold (24-65%) increase in Q13 content. In male rats receiving a single 10 mg/kg body weight dose, increased levels of peaks Q3, Q6, and Q14 were observed, while peaks Q1 and Q2 increased after acid hydrolysis. In male rats receiving a single 500 mg/kg body weight dose, peak Q14 increased. Simultaneously, peaks Q4, Q5, Q7, Q8, and Q10 disappeared in the corresponding radiochromatograms, while peaks Q3 and Q9 showed a significant decrease. Enzymatic hydrolysis did not affect the metabolite profile. High-performance liquid chromatography (HPLC) separation of bile samples from male rats receiving quinoline ring-labeled quinolone at 10 mg/kg body weight or 500 mg/kg body weight (collected at different time points, 0-24 hours) yielded six peaks (B2-B7). At different time points, peaks B6 and B7 accounted for 20-66% and 26-59% of bile excretion, respectively. For rats at 10 mg/kg body weight, the radiolabeled levels of each peak at different time points were: B2 6-15%; B5 4-15%; B3 and B4 < 5%. Only peaks B6 and B7 were detected in rat samples at 500 mg/kg body weight, but this may be due to the high detection limits in the research laboratory. After enzymatic hydrolysis, additional peaks B1, B8, B9, and B10 were detected. The disappearance of peak B7 was accompanied by the appearance of peak B10 (approximately 25%), suggesting that B7 may be a glucuronide or sulfatase product of B10. After acid hydrolysis, the radioactivity of B6 in rat bile samples treated with doses of 10 or 500 mg/kg body weight increased by 20% compared to the control group. Peaks B1, B8, and B9 were observed in rat samples from the 10 mg/kg body weight dose group, but were not detected in the 500 mg/kg body weight dose group. B10 eluted simultaneously with quinoxaline, but mass spectrometry analysis showed that its key ion had a mass 16 mass units greater than the corresponding fragment ion of quinoxaline. The study concludes that the two metabolites associated with the B10 peak are isomers of fluorobenzene ring-hydroxylated quinoline. For more complete metabolite/metabolite data on quinoline (7 metabolites in total), please visit the HSDB record page.
Biological half-life
Cannulated rats (n=5 males and n=5 females per group) were sacrificed 48 hours after administration. Cannulated bile duct rats (n=3 males per group) were sacrificed 24 hours after administration. Blood samples were collected from the jugular vein cannulation site at 0.25, 0.5, 0.75, 1, 1.5, 3, 6, 12, 24, and 48 hours after administration. Urine, feces, and bile were collected periodically throughout the study. The elimination of plasma radioactivity followed a biphasic pattern: the rapid half-life was < 1 hour and the slow half-life was 15–19 hours in the 10 mg/kg body weight dose group, while the rapid half-life was 2–3 hours and the slow half-life was 18–22 hours in the 500 mg/kg body weight dose group. There was no significant difference between the repeated-dose group and the single-dose group.

Non-Human Toxicity Values
Rabbit dermal LD50 >2000 mg/kg
Rat inhalation LC50 > 3.38 mg/L (median mass aerodynamic diameter 3.6 μm) / duration not specified/
Rat oral LD50 >5000 mg/kg

Quinoxfen is a quinoline compound with two chlorine substituents at positions 5 and 7, and a 4-fluorophenoxy substituent at position 4. It is a fungicide primarily used to control powdery mildew in cereals and belongs to the class of antifungal pesticides. Quinoxfen is an aromatic ether, belonging to the quinoline, organochlorine, and monofluorobenzene classes. Quinoxfen is mainly used to control Erysiphe graminis, the causal agent of cereal powdery mildew. It is systemic, protecting the fungus and inhibiting appressorium development through translocation, thereby preventing disease infection.

C15H8CL2FNO

308.13

306.996

124495-18-7

Quinoxyfen-d4

3391107

Crystals from heptane
Off-white solid

1.4±0.1 g/cm3

423.2±45.0 °C at 760 mmHg

105-106°

209.7±28.7 °C

0.0±1.0 mmHg at 25°C

1.648

6.29

0

3

2

20

325

0

C1=C(C=CC(=C1)OC2=CC=NC3=CC(=CC(=C32)Cl)Cl)F

WRPIRSINYZBGPK-UHFFFAOYSA-N

InChI=1S/C15H8Cl2FNO/c16-9-7-12(17)15-13(8-9)19-6-5-14(15)20-11-3-1-10(18)2-4-11/h1-8H

5,7-dichloro-4-(4-fluorophenoxy)quinoline

DE-795 QuinoxyfenDE795Legend DE 795

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~16.67 mg/mL (~54.10 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)