Mite

Absorption, Distribution and Excretion
Fenpyroximate was relatively well absorbed by rats after oral administration. Absorbed fenpyroximate was excreted predominantly via the biliary route, with lesser amounts in urine. The residual levels in organs and tissues after 168 hr were low. There was no evidence of bioaccumulation.
Groups of four male Sprague-Dawley CD rats received single dermal applications of 14C-pyrazole-fenpyroximate suspended in water at doses of 0.1, 1.0, or 5.2 mg in 1 mL on a 10 sq cm area of skin for 0.5, 1, 2, 4, 10, or 24 hr and were sacrificed at the end of the exposure period, The concentration of radiolabel in blood was very low after all applications. Excretion in urine was slight but increased with duration of exposure; after 24 hr of exposure, 0.7-0.9% of the applied dose had been excreted. Radiolabel was found in feces after 10 and 24 hr of treatment, and fecal excretion was 1.4% at a dose of 1 mg, 0.5% at 10 mg, and 0.2% at 52 mg. These results suggest that fenpyroximate is barely absorbed from the skin and is excreted via the biliary-faecal and urinary routes.
Groups of six male and six female Sprague-Dawley rats with bile duct cannulae were given a single oral dose of 2 mg/kg of (14)C-pyrazole- or (14)C-benzyl-fenpyroximate. Within 48 hr after treatment with pyrazole-labelled fenpyroximate, 47% (females) to 55% (males) of the radiolabel had been excreted in the bile, 5%, (males) to 10% (females) in urine, and 17% (females) to 28% (males) in feces. Total excretion 48 hr after treatment was about 88% for males and 73% for females. The Tmax, Cmax, and half-lives of the radiolabel in the blood of cannulated rats were similar to those of rats with no cannulae. Within 48 hr after oral administration of benzyl-labelled fenpyroximate, 47% (females) to 51% (males) of the radiolabel had been excreted in the bile, 6% (males) to 8% (females) in urine, and 28% (females) to 40% (males) in feces.
Groups of six male and six female Sprague-Dawley (Crl;CD)rats were given single doses by gavage of 2 or 400 mg/kg bw of (3-(14)C)-pyrazole-(radiochemical purity, 96.4-99.9%) or (U-(14)C)-benzyl-fenpyroximate (radiochemical purity, 99.2-99.5%) suspended in 1% aqueous Tween 80. Blood was collected from the tail vein of five rats per group at various times up to 168 hrs after dosing. In rats given 2 mg/kg bw, the concentration of radiolabel in blood peaked within 1 hr after dosing and reached a plateau, which was sustained for about 18 hrs... In the group given 400 mg/kg bw, absorption was delayed, and radiolabel was not detectable in blood within the first 12 hrs after dosing. A nearly maximal level was achieved 12-24 hrs after dosing; the plateau was sustained for 80-100 hrs ...
For more Absorption, Distribution and Excretion (Complete) data for Fenpyroximate (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
Fenpyroximate was extensively metabolized in rats; 23 metabolites were identified. No parent compound was found in the urine; metabolites found in the excreta represented 0-11% of the administered dose. Multiple pathways have been proposed for the metabolism of fenpyroximate, including oxidation, hydroxylation, demethylation, hydrolysis, and isomerization.
Fenpyroximate is metabolized extensively by hydrolytic cleavage of the oxime ether bond, hydrolysis of the tert-butyl ester, oxidation of the tert-butyl, hydroxylation of the phenoxy ring and 3-methyl, isomerization, N-demethylation, and conjugation, producing a large number of metabolites. The major metabolites identified are (E)-4-[(1,3-dimethyl-5-phenoxypyrazol-4-yl) methyleneaminooxymethyl] benzoic acid, (Z)-4-[(1,3-dimethyl-phenoxypyrazol-4yl) methyleneaminooxymethyl] benzoic acid, (E)-4-{[1,3-dimethyl-5-(4-hydroxyphenoxy) pyrazol-4-yl]methyleneaminooxymethyl} benzoic acid, 1,3-dimethyl-5-phenoxypyrazole-4-carboxylic acid, 4-hydroxymethyl benzoic acid, terephthalic acid, 4-cyano-1-methyl-5-phenoxypyrazole-3-carboxylic acid, (E)-2-{4-[(1,3-dimethyl-5-phenoxypyrazol-4-yl) methyleneaminooxymethyl] benzoyloxy}-2-methylpropanoic acid, (E)-2-{4-[1,3-dimethyl-5-(4-hydroxyphenoxy) pyrazol-4-yl] methyleneaminooxymethyl} benzoyloxy]-2-methylpropionic acid, and (E)-2-[{4-[3-hydroxymethyl-1-methyl-5-phenoxypyrazol-4-yl] methyleneaminooxymethyl} benzoyloxy]-2-methylpropionic acid.
Groups of six male and six female Sprague-Dawley rats with bile-duct cannulae were given a single oral dose of 2 mg/kg (14)C-pyrazole-labeled fenpyroximate. No parent fenpyroximate was found in bile, but metabolites (E)-4-[(1,3-dimethyl-5-phenoxypyrazol-4-yl)-methyleneaminooxy-methyl] benzoic acid, (Z)-4-[(1.3-dimethyl-5-phenoxy-pyrazol-4-yl)-methyleneaminooxy-methyl] benzoic acid, (E)-4-{[1,3-dimethyl-5-(4-hydroxyphenoxy) pyrazol-4-yl] methyleneaminooxymethyl} benzoic acid, (E)-2-{4-[(1,3-dimethyl-5-phenoxypyrazol- 4-yl) methyleneaminooxymethyl] benzoyloxy}-2-methylpropanoic acid, 1,3-dimethyl-5-(4-hydroxyphenoxy)pyrazole-4-carbaldehyde, 1,3-dimethyl-5-phenoxypyrazole-4-carboxylic acid, 3-methyl-5-phenoxypyrazole-4-carbaldehyde, 1,3-dimethyl-5-(4-hydroxyphenoxy)-pyrazole-4-carbonitrile, (E)-1,3-dimethyl-5-phenoxypyrazole-4-carbaldehydeoxime, 3-methyl-5-(4-hydroxyphenoxy)-pyrazole-4-carbaldehyde, and (E)-2-[4-[(1,3-dimethyl-5-phenoxy-pyrazol-4-yl)methyleneamniooxy-methyl]benzoyloxy]-2-methyl-propanoic acid, and conjugates of (E)-4-[(1,3-dimethyl-5-phenoxypyrazol-4-yl)-methyleneaminooxy-methyl] benzoic acid, (Z)-4-[(1.3-dimethyl-5-phenoxy-pyrazol-4-yl)-methyleneaminooxy-methyl] benzoic acid, (E)-4-{[1,3-dimethyl-5-(4-hydroxyphenoxy) pyrazol-4-yl] methyleneaminooxymethyl} benzoic acid, and 1,3-dimethyl-5-phenoxypyrazole-4-carboxylic acid were found. Total radiolabel represented less than 2% of the dose. The metabolic pathway proposed for fenpyroximate in rats is cleavage of the ester bond, hydroxylation at the phenoxypyrazole group, oxidation at the tert-butyl group, and conjugation with sulfate and glucuronide.
Groups of four male Sprague-Dawley (SLC) rats were treated with a single oral dose of 1.5 mg/kg bw (14)C-pyrazole- or (14)C-benzoyl- labeled fenpyroximate (radioactive purity, > 99%), and urinary and fecal samples were collected for 0-72 hrs. Six urinary and 17 fecal metabolites were identified by thin-layer co-chromatography with authentic samples. ... The major urinary metabolites were 1,3-dimethyl-5-phenoxypyrazole-4-carboxylic acid (7.3% of the dose), 4-cyano-1-methyl-5-phenoxy-pyrazole-3-carboxylic acid (2.5%), and terephthalic acid (3.8%). The major fecal metabolites were (E)-4-[(1,3-dimethyl-5-phenoxypyrazol-4-yl)-methyleneaminooxy-methyl] benzoic acid (4.1-11.0% of the dose), (E)-4-{[1,3-dimethyl-5-(4-hydroxyphenoxy) pyrazol-4-yl] methyleneaminooxymethyl} benzoic acid (2.9-4.2%), and (E)-2-[4-[(1,3-dimethyl-5-phenoxy-pyrazol-4-yl)methyleneamniooxy-methyl]benzoyloxy]-2-methyl-propanoic acid (3.5-4.3%); 4-hydroxymethyl benzoic acid (7.5%) was found as a precursor of terephthalic acid and (E)-2-[4-[1,3-dimethyl-5-(4-hydroxyphenoxy) pyrazol-4-yl] methyleneaminooxymethyl} benzoyloxy]-2-methylpropionic acid (2.0-9.7%) and (E)-2-[{4-[3-hydroxymethyl-1-methyl-5-phenoxypyrazol-4-yl] methyleneaminooxymethyl} benzoyloxy]-2-methylpropionic acid (3.3-4.5%) as hydroxylated bodies of (E)-2-[4-[(1,3-dimethyl-5-phenoxy-pyrazol-4-yl)methyleneamniooxy-methyl]benzoyloxy]-2-methyl-propanoic acid. The concentrations of the urinary metabolites 1,3-dimethyl-5-(4-hydroxyphenoxy)-pyrazole-4-carbonitrile and 3-methyl-5-(4-hydroxyphenoxy)-pyrazole-4-carbaldehyde and the fecal metabolites tert-butyl(E)-4-[(1,3-dimethyl-5-(4-hydroxyphenoxy)pyrazol-4-yl)methyleneaminooxymethyl] benzoate, (E)-2-[4-[(1,3-dimethyl-5-phenoxy-pyrazol-4-yl)methyleneamniooxy-methyl]benzoyloxy]-2-methyl-propanoic acid, (E)-2-[4-[1,3-dimethyl-5-(4-hydroxyphenoxy) pyrazol-4-yl] methyleneaminooxymethyl} benzoyloxy]-2-methylpropionic acid, and (E)-2-[{4-[3-hydroxymethyl-1-methyl-5-phenoxypyrazol-4-yl] methyleneaminooxymethyl} benzoyloxy]-2-methylpropionic acid were increased by enzymatic hydrolysis of the excreta with beta-glucuronidase or sulfatase.
In the present study, least 3 rats/sex/dose/time interval combination were treated with a single oral dose of (Pyrazole-(14)C) Fenpyroximate (NNI-850, purity: 99.6%), prior to collection of urine, feces, organic volatiles, and carbon dioxide. The preliminary study found no detectable carbon dioxide, and organic volatiles were either non-detectable or below quantifiable levels. ... Single oral doses were low (2 mg/kg) or high (400 mg/kg). Sacrifice time intervals after radiolabeled Fenpyroximate treatment were 12, 24, and 168 hr for low dose groups, and 12, 24, 96, 120, and 168 hr for high dose groups. Repeat dose groups received 2 mg/kg/day unlabeled Fenpyroximate for 14 days, followed by a single treatment with labeled Fenpyroximate at 2 mg/kg. This group was maintained for 168 hr before sacrifice. All 168-hr groups consisted of 5/sex, and these were used for excretion samples at intervals throughout that period. Metabolite identification was performed by comparisons of 2-dimensional TLC mobilities of excreta extracts with mobilities of a series of proposed metabolites in two sets of solvent systems (i.e. standard chromatograms by visualization under UV light were compared to autoradiograms of fecal or urinary extracts). ... A single 2 mg/kg dose found about 8% of fecal metabolites as parent compound, about 13% presumed to be the ester hydrolysis product, with other characterized metabolites accounting for about 5% or less of fecal radioactivity. Uncharacterized metabolites which remained at the origin of the 0-24 hr TLC plates of 2 mg/kg groups constituted 47-50% of fecal label, compared to 2-4% in 400 mg/kg groups, suggesting that most of the dose was absorbed and metabolized following low dose administration. ... The major identified urinary metabolite was evidently 1,3-dimethyl-5-phenoxypyrazol- 4-carboxylic acid. This compound, designated M-8, was substantially conjugated as a glucuronide. ...

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Biological Half-Life
Groups of six male and six female Sprague-Dawley (Crl;CD)rats were given single doses by gavage of 2 or 400 mg/kg bw of (3-(14)C)-pyrazole-(radiochemical purity, 96.4-99.9%) or (U-(14)C)-benzyl-fenpyroximate (radiochemical purity, 99.2-99.5%) suspended in 1% aqueous Tween 80. Blood was collected from the tail vein of five rats per group at various times up to 168 hrs after dosing. In rats given 2 mg/kg bw ... slow elimination phase with a half-life of 6-9 hrs. In the group given 400 mg/kg bw ... elimination phase with a half-life of 35-49 hrs.
Two studies used five rats/sex/group, dosed with 2 or 400 mg/kg (Pyrazole-(14)C) Fenpyroximate (NNI-850) or (Benzyl- (14)C) Fenpyroximate (NNI-850) by gavage in 1% aqueous Tween 80. Tail vein blood was collected at intervals for 7 days. Pyrazole-(14)C Study: Half-lives in blood were 8.9 hr for both M and F at 2 mg/kg. ... In contrast, 400 mg/kg led to half-lives in blood of 49 and 45 hr for M and F. ... Benzyl-(14)C Study: Half-lifes in blood were 6.1 hr and 7.9 hr for M and F, respectively, at 2 mg/kg. ... In contrast, 400 mg/kg led to half-lives in blood of 47 and 35 hr for M and F.

Non-Human Toxicity Values
LC50 Rat inhalation (female) 0.33 mg/L/4 hr /nose-only exposure/
LC50 Rat inhalation (male) 0.21 mg/L/4 hr /nose-only exposure/
LC50 Rat inhalation (female) 0.36 mg/L/4 hr /whole-body exposure/
LC50 Rat inhalation (male) 0.33 mg/L/4 hr /whole-body exposure/
For more Non-Human Toxicity Values (Complete) data for Fenpyroximate (9 total), please visit the HSDB record page.

[1]. Demographic analysis of fenpyroximate and thiacloprid exposed predatory mite Amblyseius swirskii (Acari: Phytoseiidae). PLoS One. 2018 Nov 15;13(11):e0206030.

[2]. Fenpyroximate binds to the interface between PSST and 49 kDa subunits in mitochondrial NADH-ubiquinone oxidoreductase. Biochemistry. 2012 Mar 6;51(9):1953-63.

Fenpyroximate is a pyrazole acaricide and a tert-butyl ester. It has a role as a mitochondrial NADH:ubiquinone reductase inhibitor. It derives from a hydride of a 1H-pyrazole.
Fenpyroximate is under investigation in clinical trial NCT02533336 (The Effectiveness of Non-pyrethroid Insecticide-treated Durable Wall Liners as a Method for Malaria Control in Endemic Rural Tanzania).

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Mechanism of Action
The high specificity of fenpyroximate as a miticide is not based primarily on differences in target site sensitivity since it inhibits the mitochondrial complex I from rat liver and from spider mites with less than a 10-fold difference in potency. The main mechanism of selectivity has been shown to depend on differential rates of metabolic detoxification, particularly through removal of the t-Bu group yielding the free carboxylic acid analog. This metabolite is inactive as a complex I inhibitor. This apparent hydrolysis is largely catalyzed by cytochrome PA50 through hydroxylation of the t-Bu group followed by intramolecular ester cleavage. Oxidative ester cleavage was rapid in the several mammals, fish, and insects tested but it did not occur in mites.
Parkinson's disease (PD) brains show evidence of mitochondrial respiratory Complex I deficiency, oxidative stress, and neuronal death. Complex I-inhibiting neurotoxins, such as the pesticide rotenone, cause neuronal death and parkinsonism in animal models. We have previously shown that DJ-1 over-expression in astrocytes augments their capacity to protect neurons against rotenone, that DJ-1 knock-down impairs astrocyte-mediated neuroprotection against rotenone, and that each process involves astrocyte-released factors. To further investigate the mechanism behind these findings, we developed a high-throughput, plate-based bioassay that can be used to assess how genetic manipulations in astrocytes affect their ability to protect co-cultured neurons. We used this bioassay to show that DJ-1 deficiency-induced impairments in astrocyte-mediated neuroprotection occur solely in the presence of pesticides that inhibit Complex I (rotenone, pyridaben, fenazaquin, and fenpyroximate); not with agents that inhibit Complexes II-V, that primarily induce oxidative stress, or that inhibit the proteasome. This is a potentially PD-relevant finding because pesticide exposure is epidemiologically-linked with an increased risk for PD. Further investigations into our model suggested that astrocytic GSH and heme oxygenase-1 antioxidant systems are not central to the neuroprotective mechanism.
... In this study, ...the in vitro toxicity and mechanism of action of several putative complex I inhibitors that are commonly used as pesticides/ tebunfenpyrad. A similar order of potency was observed for reduction of ATP levels and competition for (3)H-dihydrorotenone (DHR) binding to complex I, with the exception of pyridaben (PYR). Neuroblastoma cells stably expressing the /rotenone/ (ROT)-insensitive NADH dehydrogenase of Saccharomyces cerevisiae (NDI1) were resistant to these pesticides, demonstrating the requirement of complex I inhibition for toxicity. ... PYR was a more potent inhibitor of mitochondrial respiration and caused more oxidative damage than ROT. The oxidative damage could be attenuated by NDI1 or by the antioxidants alpha-tocopherol and coenzyme Q(10). PYR was also highly toxic to midbrain organotypic slices. These data demonstrate that, in addition to ROT, several commercially used pesticides directly inhibit complex I, cause oxidative damage, and suggest that further study is warranted into environmental agents that inhibit complex I for their potential role in Parkinson's Disease.

C24H27N3O4

421.49

421.2

111812-58-9

(E)-Fenpyroximate;134098-61-6

9576412

White crystalline powder

1.1±0.1 g/cm3

546.2±60.0 °C at 760 mmHg

99-102ºC

284.1±32.9 °C

0.0±1.5 mmHg at 25°C

1.561

6.44

74.94

0

6

9

31

592

0

O(C1C=CC=CC=1)C1N(N=C(C=1C=NOCC1C=CC(=CC=1)C(=O)OC(C)(C)C)C)C

YYJNOYZRYGDPNH-MFKUBSTISA-N

InChI=1S/C24H27N3O4/c1-17-21(22(27(5)26-17)30-20-9-7-6-8-10-20)15-25-29-16-18-11-13-19(14-12-18)23(28)31-24(2,3)4/h6-15H,16H2,1-5H3/b25-15+

tert-butyl 4-[[(E)-(1,3-dimethyl-5-phenoxypyrazol-4-yl)methylideneamino]oxymethyl]benzoate

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
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10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
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