EMAMECTIN BENZOATE   中文名称: 甲胺基阿维菌素苯甲酸盐

依美菌素苯甲酸酯（MK-244；2.5–40 μM；12 和 24 小时）会以剂量和时间依赖性方式降低细胞活力 [1]。 16HBE 细胞暴露于 2.5–20 μM 的 emmemactin 苯甲酸盐 24 小时，会导致 DNA 损伤和 ROS 生成 [1]。 Emamectin Benzoate（2.5 – 20 μM；12 小时）可提高 cleaved-PARP、Bax/Bcl-2、caspase-3、caspase-9 和细胞色素 c 的水平 [1]。甲维盐苯甲酸酯（2.5、5、10、15 μM；72 小时）的 IC50 为 3.72 μM，可降低 Trichopodia exigua Tn5B1-4 细胞的活力。当暴露于甲维盐苯甲酸盐时，缩合物和细胞色素会发生核染色[2]。检查[1]

在肝组织中，甲维盐苯甲酸盐（MK-244；侧壁；25-100 mg/kg/天；持续 14 天）会显着增加氧化损伤[3]。

细胞活力测定[1]
细胞类型： 人正常支气管上皮细胞系 16HBE
测试浓度： 2.5, 5, 7.5, 10, 15, 20 ，40 μM
孵育时间：12 和 24 小时
实验结果：细胞活力以时间和剂量依赖性方式减弱12小时时的IC50值在24小时内分别为11.88μM和9.67μM。

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细胞凋亡分析 [1]
细胞类型：人类正常支气管上皮细胞系 16HBE
测试浓度： 2.5、5、10、 20 μM
孵育时间：24小时
实验结果：诱导细胞凋亡并引起染色质收缩和核碎裂。

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蛋白质印迹分析 [1]
细胞类型： 人类正常支气管上皮细胞系 16HBE
测试浓度： 2.5、5、10 ，20 μM
孵育时间：12 小时
实验结果：细胞色素-c、caspase-3 和 cas-pase- 9 个水平增加，Cleavage-PARP、Bax/Bcl-2。

Animal/Disease Models: 10weeks old Swiss albino male mice (25-30 g) [3]
Doses: 25, 50, 100 mg/kg
Route of Administration: oral; daily; lasting for 14 days
Experimental Results: Lead to significant induction of oxidation in liver tissue injury, as evidenced by increased TBARS levels and diminished GSH levels.

Absorption, Distribution and Excretion
There were 2 dosing groups, each consisting of 2 male beagles. Group 1 received 0.5 mg/kg of (3)H-MK-0243 benzoate (1 mL/kg in 5% ethanol ... 0.239 mCi/mg; 98.8% radiochemically pure) on day 1 and 0.5 mg/kg of (3)H-MK-0243 HCl (1 mL/kg in deionized water ... 0.229 mCi/mg; 98.7% radiochemically pure) on day 15. Dosing was reversed for Group 2. Body weights were determined before each dose. 2 mL of blood was withdrawn for drug level determinations following each dose at 0.5, 1, 2, 4, 6, 8, 24, 48, 96 and 168 hr. Urine and feces were collected for drug level analysis at 0 to 24 and 72 to 96 hr. There was no evidence of drug effects. The mean plasma half lives for the benzoate and HCl salts were 35.7 +/- 3.4 hr and 35.5 +/- 4.4 hr, respectively. The mean plasma approximate area under the curve (AUC) for the benzoate and HCl salts was 4479 +/- 1476 and 4574 +/- 1514 ng/g plasma/7days. The mean peak plasma MAB1a (the major component of MK-0243 at 90 to 95%) levels were ~100 ng equivalents/g plasma, occurring at ~6 hr for either salt. Combined fecal and urine recoveries during the 1st and 4th days were ~40% and 0.01% of the dose, respectively. It is concluded that the 2 salts are bioequivalent in male beagle dogs.
The dermal absorption of the experimental avermectin insecticide emamectin benzoate was studied in the Rhesus monkey. Dermal absorption was calculated by comparing radioactivity levels in excreta following dermal application of the compound with those following administration of an equivalent intravenous dose. After iv administration of 300 ug (3)H-MAB1a (prepared as a 1:1 solution of propylene glycol:saline) to three monkeys, plasma levels decreased biphasically with a rapid decline in radioactivity during the first 15 min followed by a slower decline to background. By 7 days post-dose, approximately 90% and 5% of the administered radioactivity was recovered in the feces and urine, respectively. After a washout period, 300 micrograms [(3)H]MAB1a (dissolved in emulsifiable concentrate) was applied topically to the shaved forearm of the same monkeys. Following a 10-hr exposure period, approximately 90% of the radioactivity was recovered in a soap and water wash of the exposed forearms. Although plasma radioactivity levels generally remained below background levels, approximately 1.5% of the applied dose was recovered in the excreta. Dermal absorption of [()3H]emamectin benzoate was calculated as 1.6%. The low dermal penetration of emamectin benzoate indicates that minimal actual exposure of agricultural workers to this compound will occur.
The aims of this study were to investigate the content of emamectin in blood, mucus and muscle following field administration of the recommended dose, and correlation with sea lice infection on the same fish (elimination study). The tissue distribution of tritiated emamectin benzoate after a single oral dose in Atlantic salmon was also investigated by means of whole-body autoradiography and scintillation counting (distribution study). In the elimination study, concentrations of emamectin benzoate reached maximum levels of 128, 105 and 68 ng/g (p.p.b.) for blood, mucus and muscle respectively, on day 7, the last day of administration. From day 7, the concentration in the blood declined until concentration was less than the limit of detection on day 77. The concentration was higher in mucus compared with plasma (P < 0.05) except on days 7 and 21. The concentration of emamectin benzoate decreased gradually from the end of treatment (day 7) to day 70 with half-lives of 9.2, 10.0 and 11.3 days in muscle, plasma and mucus respectively. The distribution study demonstrated a high quantity of radioactivity in mucous membranes (gastrointestinal tract, gills) throughout the observation period (56 days). Activity was high in the epiphysis, hypophysis and olfactory rosette throughout the study. The highest activity was observed in the bile, indicating this to be an important route for excretion. The distribution study confirmed the results from the elimination study with respect to concentrations in blood, skin mucous and muscle.
Atlantic salmon (approximately 1.3 kg) maintained in tanks of seawater at 5 +/- 1 degrees C were dosed with 3H-emamectin B1 benzoate in feed at a nominal rate of 50 ug of emamectin benzoate/kg/day for 7 consecutive days. Tissues, blood, and bile were collected from 10 fish each at 3 and 12 hr and at 1, 3, 7, 15, 30, 45, 60, and 90 days post final dose. Feces were collected daily from the tanks beginning just prior to dosing to 90 days post final dose. The total radioactive residues (TRR) of the daily feces samples during dosing were 0.25 ppm maximal, and >97% of the TRR in pooled feces covering the dosing period was emamectin B1a. Feces TRR then rapidly declined to approximately 0.05 ppm by 1 day post final dose. The ranges of mean TRR for tissues over the 90 days post dose period were as follows: kidney, 1.4-3 ppm; liver, 1.0-2.3 ppm; skin, 0.04-0.09 ppm; muscle, 0.02-0.06 ppm; and bone, <0.01 ppm. The residue components of liver, kidney, muscle, and skin samples pooled by post dose interval were emamectin B1a (81-100% TRR) and desmethylemamectin B1a (0-17% TRR) with N-formylemamectin B1a seen in trace amounts (<2%) in some muscle samples. The marker residue selected for regulatory surveillance of emamectin residues was emamectin B1a. The emamectin B1a level was quantified in individual samples of skin and muscle using HPLC-fluorometry and was below 85 ppb in all samples analyzed (3 hr to 30 days post dose).
For more Absorption, Distribution and Excretion (Complete) data for EMAMECTIN (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
Atlantic salmon (approximately 1.3 kg) maintained in tanks of seawater at 5 +/- 1 degrees C were dosed with [(3)H]emamectin B1 benzoate in feed at a nominal rate of 50 ug of emamectin benzoate/kg/day for 7 consecutive days. Tissues, blood, and bile were collected from 10 fish each at 3 and 12 hr and at 1, 3, 7, 15, 30, 45, 60, and 90 days post final dose. Feces were collected daily from the tanks beginning just prior to dosing to 90 days post final dose. The total radioactive residues (TRR) of the daily feces samples during dosing were 0.25 ppm maximal, and >97% of the TRR in pooled feces covering the dosing period was emamectin B1a. Feces TRR then rapidly declined to approximately 0.05 ppm by 1 day post final dose. The ranges of mean TRR for tissues over the 90 days post dose period were as follows: kidney, 1.4-3 ppm; liver, 1.0-2.3 ppm; skin, 0.04-0.09 ppm; muscle, 0.02-0.06 ppm; and bone, <0.01 ppm. The residue components of liver, kidney, muscle, and skin samples pooled by post dose interval were emamectin B1a (81-100% TRR) and desmethylemamectin B1a (0-17% TRR) with N-formylemamectin B1a seen in trace amounts (<2%) in some muscle samples. The marker residue selected for regulatory surveillance of emamectin residues was emamectin B1a. The emamectin B1a level was quantified in individual samples of skin and muscle using HPLC-fluorometry and was below 85 ppb in all samples analyzed (3 hr to 30 days post dose).
...a single mammalian metabolite has been identified. This metabolite is characterized as an N-demethylation byproduct of emamectin.
The metabolism of (3)H/(14)C-labeled 4"-deoxy-4"-epimethylaminoavermectin B1a (MAB1a) benzoate, the major homologue (>/=90%) of the avermectin insecticide emamectin benzoate, was studied in laying chickens. Ten Leghorn hens (Gallus domesticus) were orally dosed once daily for 7 days (1 mg/kg of body weight/day). Eggs and excreta were collected daily, and eggs were subsequently separated into whites and yolks. Chickens were euthanized within 20 hr after the last dose, and liver, kidney, heart, muscle, fat, ovaries, gizzard, gastrointestinal tract and contents, and carcass were collected. Approximately 70 and 6% of the total administered dose were recovered in the excreta plus gastrointestinal tract and contents and in the tissues plus eggs, respectively. Two novel metabolites, i.e. the 24-hydroxymethyl derivative of the parent compound (24-hydroxymethyl-4"-deoxy-4"-epimethylaminoavermectin B1a) and the N-demethylated derivative of 24-hydroxymethyl-4"-deoxy-4"-epimethylaminoavermectin B1a (24-hydroxymethyl-4"-deoxy-4"-epiaminoavermectin B1a), were identified. In addition, eight fatty acid conjugates of each of these two metabolites, comprising 8-75% of total radioactive residues in tissues and eggs, were isolated and identified. Although this represents some of the most extensive in vivo fatty acid conjugation to a xenobiotic reported to date, potential human exposure to MAB1a residues from consumption of chicken would be extremely low, because the dosage level in this study was approximately 1000-fold greater than the MAB1a residue levels seen in crops and because the majority of the applied dose was recovered in the excreta. Based on these findings, the avian biotransformation of MAB1a differs substantially from the mammalian biotransformation.
While emamectin benzoate is not extensively metabolized in mammals, the limited information on the metabolites of emamectin benzoate suggests that metabolism does not result in the detoxification of emamectin benzoate. One plant metabolite of emamectin benzoate is somewhat more toxic than emamectin benzoate itself.

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Biological Half-Life
Emamectin benzoate was rapidly cleared from plasma /of rats/ with half-lives ranging from about 15 to 28 hours after oral or intravenous dosing.
Emamectin benzoate is a relatively large molecule (actually a mixture of four closely related molecules) which is not completely absorbed on oral administration, is poorly absorbed by the dermal administration, and rapidly eliminated in the feces with whole-body half-lives of about 1.5 days.
The tissue distribution of tritiated emamectin benzoate after a single oral dose in Atlantic salmon was also investigated by means of whole-body autoradiography and scintillation counting (distribution study). The concentration of emamectin benzoate decreased gradually from the end of treatment (day 7) to day 70 with half-lives of 9.2, 10.0 and 11.3 days in muscle, plasma and mucus respectively.

[1]. Chenguang Niu, et al. Toxic effects of the Emamectin Benzoate exposure on cultured human bronchial epithelial (16HBE) cells. Environ Pollut. 2020 Feb;257:113618.
[2]. Shaorong Luan, et al. Emamectin benzoate induces ROS-mediated DNA damage and apoptosis in Trichoplusia Tn5B1-4 cells. Chem Biol Interact. 2017 Aug 1;273:90-98.
[3]. Özge Temiz, et al. Biopesticide emamectin benzoate in the liver of male mice: evaluation of oxidative toxicity with stress protein, DNA oxidation, and apoptosis biomarkers. Environ Sci Pollut Res Int. 2020 Jun;27(18):23199-23205.

Description
Emamectin B1a is a member of emamectins.
The avermectins are a series of macrocyclic lactone derivatives with potent anthelmintic properties. A commonly used therapy in recent times has been based on oral or parenteral administration of avermectins, which are macrocyclic lactones produced by fermentation of various, carefully prepared laboratory broths using the soil micro-organism Streptomyces avermitilis. They show activity against a broad range of nematodes and arthropod parasites of domestic animals at dose rates of 300 microgram/kg or less. Unlike the macrolide or polyene antibiotics, they lack significant antibacterial or antifungal activity. (L829)

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Mechanism of Action
Emamectin benzoate is the 4'-deoxy-4'-epi-methyl-amino benzoate salt of avermectin B1 (abamectin), which is similar structurally to natural fermentation products of Streptomyces avermitilis. Emamectin benzoate is being developed as a newer broad-spectrum insecticide for vegetables and has a very low application rate. The mechanism of action involves stimulation of high-affinity GABA receptors and a consequent increase in membrane chloride ion permeability.
Overexpression of P-glycoproteins (Pgps) is assumed to be a principal mechanism of resistance of nematodes and arthropods to macrocyclic lactones. Quantitative RT-PCR (Q-RT-PCR) was used to demonstrate changes in transcription levels of two putative P-glycoprotein genes, designated here as SL0525 and SL-Pgp1, in sea lice (Lepeophtheirus salmonis) following exposure to emamectin benzoate (EMB). Pre-adult L. salmonis were challenged in an EMB bioassay for 24 hr and gene expression was studied from lice surviving EMB concentrations of 0, 10, and 30 ppb. Gene expression was measured using Q-RT-PCR with elongation factor 1 (eEF1alpha) as an internal reference gene. The results show that both target genes, SL0525 and SL-Pgp1, had significantly increased levels of expression with exposure to 10ppb EMB (p=0.11 and p=0.17, respectively) whereas the group exposed to 30 ppb was on the verge of being significant (p=0.053) only in the expression of SL-Pgp1. Gene expression for SL0525 and SL-Pgp1 were increased over five-fold at 10 ppb EMB. Therefore, the upregulation of these target genes may offer protection by increasing Pgp expression when lice are exposed to EMB. Optimized Q-RT-PCR can be used to determine if over-expression of these genes could be the basis for development of resistance in sea lice and thus allow suitable alternative chemotherapeutic options to be assessed.
Macrocyclic lactones, including avermectins and milbemycins, are novel parasiticides and insecticides that are produced through fermentation by soil-dwelling microorganisms. Although various macrocyclic lactones may differ in their potency and safety, all of them are believed to share common pharmacologic/toxicologic mechanisms, i.e. leading to paralysis and death of parasites and other target organisms via the activation of a glutamate-gated chloride channel in the invertebrate nerve and muscle cells and/or through the effect on gamma-aminobutyric acid (GABA) receptors. Ivermectin is the first macrocyclic lactone that was released for use in both animals and humans, and has demonstrated both excellent efficacy and high tolerability in the treatment of parasite infestations. Other macrocyclic lactones, such as abamectin, emamectin, and moxidectin were subsequently commercialized and have been used as insecticides and acaricides for crop protection or parasiticides for animal health.

C56H81NO15

1008.2401

885.523

155569-91-8

11549937

White to off-white powder
Off-white crystalline powder

141-146ºC

4.628

206.57

3

14

9

63

1750

20

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CXEGAUYXQAKHKJ-NSBHKLITSA-N

InChI=1S/C49H75NO13/c1-12-26(2)44-29(5)18-19-48(63-44)24-35-21-34(62-48)17-16-28(4)43(27(3)14-13-15-33-25-56-46-42(51)30(6)20-36(47(52)59-35)49(33,46)53)60-40-23-38(55-11)45(32(8)58-40)61-39-22-37(54-10)41(50-9)31(7)57-39/h13-16,18-20,26-27,29,31-32,34-46,50-51,53H,12,17,21-25H2,1-11H3/b14-13+,28-16+,33-15+/t26-,27-,29-,31-,32-,34+,35-,36-,37-,38-,39-,40-,41-,42+,43-,44+,45-,46+,48+,49+/m0/s1

(1'R,2R,3S,4'S,6S,8'R,10'E,12'S,13'S,14'E,16'E,20'R,21'R,24'S)-2-[(2S)-butan-2-yl]-21',24'-dihydroxy-12'-[(2R,4S,5S,6S)-4-methoxy-5-[(2S,4S,5S,6S)-4-methoxy-6-methyl-5-(methylamino)oxan-2-yl]oxy-6-methyloxan-2-yl]oxy-3,11',13',22'-tetramethylspiro[2,3-dihydropyran-6,6'-3,7,19-trioxatetracyclo[15.6.1.14,8.020,24]pentacosa-10,14,16,22-tetraene]-2'-one

Emamectin benzoate; Avermectin b1, 4''-deoxy-4''-(methylamino)-, (4''R)-, benzoate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

DMSO : ≥ 31 mg/mL

配方 1 中的溶解度: ≥ 2.08 mg/mL (Infinity mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (Infinity mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (Infinity mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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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));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
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；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。