Absorption, Distribution and Excretion
Following oral application to rats, elimination is rapid. Unmetabolized famoxadone was the major component in the feces; mono- (at 4'-phenoxyphenyl) and di- (also at 4-phenylamino) hydroxylated famoxadone were the primary fecal metabolites. In urine, products arising from cleavage of the heterocyclic ring were found. In goats and hens, there was little residue in the tissues; the majority of the administered famoxadone (about 60%) was unmetabolized and recovered in the feces. Metabolism was complex, involving hydroxylation, cleavage of the oxazolidinedione-aminophenyl linkage, cleavage of the phenoxyphenyl ether linkage and opening of the oxazolidinedione ring.
Ten groups of 4 or 5 Crl:CD/BR (Sprague-Dawley) albino rats per sex received a single oral gavage dose of [14C-PA]DPX-JE874 at 5 or 100 mg/kg. One group (G) of 5 per sex had been exposed (oral gavage) to non-radiolabelled DPX-JE874 for fourteen consecutive days prior to the radiolabelled dose. Two other groups (B (4/sex) and E (5/sex)) received a single dose (oral gavage) of [14C-POP]DPX-JE874 at 100 mg/kg. Groups A, B, and C: the absorption half-lives of [14C-PA]DPX-JE874 in whole blood and plasma increased from 0.8 - 1.2 hours to 3.5 - 7.1 hours as the dose increased from 5 to 100 mg/kg. Absorption half-lives of [14C-POP]DPX-JE874 at 100 mg/kg were 0.4 to 1.4 hours. Elimination half-lives were 2 to 3 fold slower in whole blood compared to plasma with [14C-PA]DPX-JE874 (indication of binding to red blood cells). No indication of binding with [14C-POP]DPX-JE874. Groups D, E, F, G: No accumulation of [14C-PA]DPX-JE874 residues in organs and tissues was observed at 5 and 100 mg/kg 120 hours post-treatment. [14C-POP]DPX-JE874 treated animals (Group E, 100 mg/kg) showed highest radioactivity in fat (< 2 ppm). Gonads, uterus, adrenals, and bone marrow also contained slightly increased levels of 14C-residues (< 2 ppm) (possibly associated with body fat adhering to the tissues). > 75% of administered radiolabel was excreted in feces and less than 10% in urine during 24 hours post-dosing. There was no significant difference in the elimination profile between single (D, E, and F) and multiple (G) dosings, between sexes, nor between [14CPA]DPX-JE874 and [14C-POP]DPX-JE874. ... Groups H and I: Liver and fat were the two primary tissues for distribution of [14C-PA]DPX-JE874 residues at 5 hours (5 mg/kg) and 14 hours (100 mg/kg) post-dosing. At 36 hours (5 mg/kg) and 48 hours (100 mg/kg), liver was the only tissue containing slightly elevated residues.
Seven rats per sex received a single oral gavage dose of [14C-PA]DPX-JE874 or [14C-POP]DPX-JE874 at 5 mg/kg. The animals had biliary and duodenal cannulae surgically implanted 3 days prior to treatment. Bile was collected continuously and sampled 1, 3, 6, 10, 16, 24, 36, and 48 hours post-dosing. Urine and feces were collected 12, 24, and 48 hours after dosing. After the final urine and feces collection, cage washes were collected and analyzed. Blood was collected from all animals at termination (48 hours post-treatment). Carcasses were homogenized and analyzed for radioactivity. 30% to 39% of administered radiolabel was excreted in bile 1 to 10 hours post-dosing. Higher amounts of [14C-POP]DPX-JE874 (39%) than of [14C-PA]DPX-JE874 (31%) were excreted in males. The average urinary excretion of radiolabel was from 2% to 6% of administered dose. 56% to 65% of administered dose was excreted in feces. 0.22% and 0.31% of administered dose was found in blood of [14C-PA]DPX-JE874 treated males and females respectively at termination. 0.03% was found in blood of both males and females treated with [14C-POP]DPX-JE874. The average amount of radiolabel in carcasses ranged from 0.4% to 3.0%.
Six male beagle dogs received a single oral gavage dose of [14C-PA]DPX-JE874 at 15 mg/kg. 3 animals (Group A) were used for pharmacokinetic sampling (sacrificed at 96 hours post-dose), 3 others (Group B) were used for tissue distribution evaluation at the peak plasma concentrations (sacrificed 2 hours post-dose) observed in Group A. The final one was used as vehicle control (Group C) (sacrificed at 96 hours). The mean recovery of radioactivity from Group A dogs during 96 hours post-dosing was 7.67% in urine, 70.3% in feces, and 0.74% in cage wash and cage wipes. Peak mean excretion of radioactivity occurred during 24 to 48 hrs post-dosing in urine and during 12-24 hours in feces. ... Group mean radioactivity concentration in plasma peaked 2 hours post-dosing at 1.53 ppm and at 4 hours in RBCs (0.626 ppm). At 96 hours, values were 0.597 ppm (plasma) and 0.648 ppm (RBCs). The highest mean concentrations of radioactivity were detected in liver (1.34 ppm) and mesenteric fat (0.945 ppm) at the 96-hour sacrifice. Mean levels in aqueous humor, eye, and eye remainder were 0.091 ppm, 0.135 ppm, and 0.173 ppm, respectively. In Group B animals (2-hour sacrifice), the highest mean concentrations of radioactivity were found in liver (4.45 ppm), mesenteric fat (2.80 ppm), plasma (0.999 ppm), and RBCs (0.413 ppm). Residues in the aqueous humor, eye, and eye remainder were 0.061 ppm, 0.106 ppm, and 0.131 ppm, respectively.
For more Absorption, Distribution and Excretion (Complete) data for FAMOXADONE (6 total), please visit the HSDB record page.

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Metabolism / Metabolites
Hydroxylation of the two phenyl rings at the para position is the major routes of metabolism.
... Groups of 4 or 5 Crl:CD/BR (Sprague-Dawley) albino rats per sex received a single oral gavage dose of [14C-PA]DPX-JE874 at 5 or 100 mg/kg ... /or/ a single dose (oral gavage) of [14C-POP]DPX-JE874 at 100 mg/kg. ... Three radioactive components were observed in feces of both [14C-PA] and [14C-POP] treated animals. Unmetabolized 14C-DPX-JE874 was the major component. The other two were monohydroxylated (IN-KZ007) and di para hydroxylated (IN-KZ534) DPX-JE874. One major radioactive component (a sulfate conjugate) was observed in urine of [14C-POP] treated animals. The primary metabolite in urine from [14C-PA] treated animals coincided with 4-acetoxyaniline (HPLC).

[1]. D T Likas, et al. Rapid Gas Chromatographic Method for the Determination of Famoxadone, Trifloxystrobin and Fenhexamid Residues in Tomato, Grape and Wine Samples. J Chromatogr A. 2007 May 25;1150(1-2):208-14.

5-methyl-5-(4-phenoxyphenyl)-3-(phenylamino)-1,3-oxazolidine-2,4-dione is a member of the class of oxazolidinones that is 1,3-oxazolidine-2,4-dione in which the hydrogen attached to the nitrogen is substituted by a phenylamino group and the hydrogens at position 5 are substituted by methyl and 4-phenoxyphenyl groups. It is an aromatic ether, a carbohydrazide and an oxazolidinone.
Famoxadone is a oxazolidinedione fungicide to protect agricultural products against various fungal diseases including downy mildew and blights on fruiting vegetables, tomatoes, potatoes, curcurbits, lettuce and grapes. It is used in combination with cymoxanil. It has a low aqueous solubility, low risk of leaching to groundwater and is non-volatile. It is not persistent in soil or water. Whilst it has a low mammalian toxicity there is a slight concern regarding its ability to bioaccumulate. It is considered to be a neurotoxicant and is a known eye and skin irritant. It is highly toxic to fish and aquatic invertebrates and moderately toxic to other aquatic organisms, earthworms and honeybees.

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Mechanism of Action
Famoxadone is an extremely potent inhibitor of mitochondrial electron transport acting at complex III in mitochondria from fungi, plants and mammals ... The site of inhibition is cytochrome b within the Qo domain which prevents transfer of electrons from cytochrome b to cytochrome c1.

C22H18N2O4

374.39

374.126

131807-57-3

213032

Pale cream powder

1.3±0.1 g/cm3

491.3±55.0 °C at 760 mmHg

140.3-141.8ºC

250.9±31.5 °C

0.0±1.2 mmHg at 25°C

1.659

4.76

1

5

5

28

563

0

CC1(C2=CC=C(C=C2)OC3=CC=CC=C3)C(=O)N(C(=O)O1)NC4=CC=CC=C4

PCCSBWNGDMYFCW-UHFFFAOYSA-N

InChI=1S/C22H18N2O4/c1-22(16-12-14-19(15-13-16)27-18-10-6-3-7-11-18)20(25)24(21(26)28-22)23-17-8-4-2-5-9-17/h2-15,23H,1H3

3-anilino-5-methyl-5-(4-phenoxyphenyl)-1,3-oxazolidine-2,4-dione

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 : 100 mg/mL (267.10 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.68 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.68 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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