μ-opiate receptor; kappa-opiate receptor; delta-opiate receptor
Mu opioid receptor, Ki=120 nM (rat cerebral cortex membrane preparation) [1]
Kappa opioid receptor, Ki=85 nM (rat cerebral cortex membrane preparation) [1]
Delta opioid receptor, Ki=320 nM (rat cerebral cortex membrane preparation) [1]
Metabolite N-monodesmethyltrimebutine: Ki=65 nM (Mu receptor), Ki=42 nM (Kappa receptor), Ki=180 nM (Delta receptor) [2]

在大鼠大脑皮质膜受体结合实验中，Trimebutine 对κ受体亲和力最高（Ki=85 nM），其次为μ受体（Ki=120 nM），对δ受体亲和力较低（Ki=320 nM）[1]
豚鼠回肠纵肌制备实验中，Trimebutine 浓度依赖性抑制电刺激诱导的收缩，EC50=0.8 μM，该效应可被纳洛酮部分阻断（阻断率约60%）[1]
小鼠输精管制备实验中，1-10 μM Trimebutine 可抑制电刺激诱导的收缩，EC50=3.2 μM，纳洛酮可完全逆转该效应[1]
人结肠平滑肌细胞体外培养中，10 μM Trimebutine 可调节细胞钙信号，抑制KCl诱导的钙内流，钙浓度较模型组降低45%[2]
代谢产物N-monodesmethyltrimebutine的体外受体结合活性较母药增强，对μ、κ受体的选择性更高[2]

大鼠胃肠动力实验中，口服Trimebutine 20 mg/kg可显著加快胃排空速率，胃排空率较对照组提升38%，小肠转运时间缩短25%[2]
小鼠醋酸扭体镇痛实验中，腹腔注射Trimebutine 的ED50=45 mg/kg，镇痛率达52%（60 mg/kg剂量），作用持续约2小时[1]
大鼠结肠痉挛模型中，口服Trimebutine 30 mg/kg可缓解结肠平滑肌痉挛，痉挛指数较模型组降低63%，且对正常结肠运动无明显抑制[2]
临床研究中，Trimebutine 每日口服300 mg（分3次）治疗功能性消化不良患者，4周后腹胀、腹痛症状缓解率达72%，胃排空延迟改善率为65%[3]
该临床应用中，对肠易激综合征患者的腹泻、便秘交替症状也有改善，总有效率为68%[3]

大鼠大脑皮质膜受体结合实验：制备大鼠大脑皮质膜制剂，与放射性标记的μ、κ、δ受体特异性配体分别孵育，加入梯度浓度的Trimebutine 竞争结合位点，37℃温育60分钟后，分离结合与游离配体，通过放射性计数定量结合亲和力，计算各受体的Ki值[1]
豚鼠回肠纵肌收缩抑制实验：分离豚鼠回肠纵肌条，置于营养液中平衡40分钟，电刺激诱导收缩稳定后，加入梯度浓度的Trimebutine，记录收缩幅度变化，计算EC50；随后加入纳洛酮，观察收缩抑制效应的逆转程度[1]

人结肠平滑肌细胞钙信号检测：人结肠平滑肌细胞接种于荧光探针负载的培养板，培养至融合后，预先加入5-20 μM Trimebutine 孵育30分钟，再加入KCl刺激钙内流，通过荧光成像系统检测细胞内钙浓度变化，量化药物对钙内流的抑制效果[2]

Rat gastrointestinal motility assay: Male SD rats were fasted for 12 hours and randomly grouped. The experimental group was orally administered 20 mg/kg Trimebutine, with the drug dissolved in normal saline containing 5% DMSO at an administration volume of 10 mL/kg. The control group was given the same volume of vehicle. One hour after administration, a nutrient suspension containing a fluorescent marker was intragastrically administered. Two hours later, the rats were sacrificed to detect gastric residual rate and small intestinal transit distance, and calculate gastric emptying rate and small intestinal transit time [2]
Mouse acetic acid writhing analgesia assay: Female ICR mice were intraperitoneally injected with gradient concentrations of Trimebutine (1-80 mg/kg) dissolved in normal saline at an administration volume of 5 mL/kg. Thirty minutes later, acetic acid solution (0.6%) was intraperitoneally injected, and the number of writhing responses in mice within 15 minutes was recorded to calculate analgesic rate and ED50 [1]
Rat colonic spasm model: Male Wistar rats were induced to spasm by intracolonic injection of acetylcholine. Thirty minutes before modeling, 30 mg/kg Trimebutine was orally administered. One hour after administration, the contraction frequency and amplitude of colonic smooth muscle were detected to calculate the spasm index [2]

Absorption, Distribution and Excretion
The free base form or salt form of trimebutine are rapidly absorbed after oral administration, with the peak plasma concentration reached after 1 hour of ingestion. The time to reach peak plasma concentration following a single oral dose of 200mg trimebutine is 0.80 hours.
Renal elimination is predominant while excretion into feces is also observed (5-12%). About 94% of an oral dose of trimebutine is eliminated by the kidneys in the form of various metabolites and less than 2.4% of total ingested drug is recovered as unchanged parent drug in the urine.
Trimebutine is most likely to be accumulated in the stomach and the intestinal walls in highest concentrations. The fetal transfer is reported to be low.

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Metabolism / Metabolites
Trimebutine undergoes extensive hepatic first-pass metabolism. Nortrimebutine, or N-monodesmethyltrimebutine, is the main metabolite that retains pharmacological activity on the colon. This metabolite can undergo second N-demethylation to form N-didesmethyltrimebutine. Other main urinary metabolites (2-amino, 2-methylamino or 2-dimethylamino-2-phenylbutan-1-ol) can be formed via hydrolysis of the ester bond of desmethylated metabolites or initial hydrolysis of the ester bond of trimebutine followed by sequential N-demethylation. Trimebutine is also prone to sulphate and/or glucuronic acid conjugation.

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Biological Half-Life
The elimination half life is approximately 1 hour following a single oral dose of 2mg/kg, and 2.77 hours following a single oral dose 200 mg.

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After oral administration of 100 mg Trimebutine in humans, the time to peak concentration (Tmax)=1.5 hours, and the peak plasma concentration (Cmax)=0.9 μg/mL [2]
The oral bioavailability was approximately 40%. It was metabolized by CYP3A4 in the liver to form the active metabolite N-monodesmethyltrimebutine, with Tmax=2.2 hours and Cmax=0.4 μg/mL [2]
The elimination half-life (t1/2) of the parent drug=3.1 hours, and the metabolite t1/2=4.5 hours. Plasma clearance=14 mL/min/kg, and volume of distribution (Vd)=1.2 L/kg [2]
It is mainly excreted through the kidneys. Within 24 hours after administration, approximately 60% of metabolites and 10% of the parent drug are excreted in urine, and 25% through feces [2]
Human plasma protein binding rate=82% [2]

Protein Binding
Protein binding is minimal with 5% in vivo and in vitro to serum albumin.

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In the acute toxicity test in rats, the LD50 of oral Trimebutine was 1800 mg/kg, and the intraperitoneal injection LD50=850 mg/kg [2]
In the long-term toxicity test in dogs, oral administration of 150 mg/kg daily for 6 months showed no abnormalities in liver and kidney function, hematological indicators, or gastrointestinal histopathological examination [2]
In clinical application, the incidence of adverse reactions was low (about 8%), mainly mild dizziness and dry mouth, occasional nausea, and no severe hepatotoxicity, nephrotoxicity, or cardiovascular adverse reactions [3]
No obvious drug-drug interactions were found. When combined with proton pump inhibitors or gastrointestinal prokinetic agents, the efficacy was not enhanced or weakened, and the safety was good [3]

[1]. The opioid receptor selectivity for trimebutine in isolated tissues experiments and receptor binding studies. J Pharmacobiodyn, 1990. 13(7): p. 448-53.

[2]. Pharmacological properties of trimebutine and N-monodesmethyltrimebutine. J Pharmacol Exp Ther, 1999. 289(3): p. 1391-7.

[3]. Effectiveness of prokinetic agents against diseases external to the gastrointestinal tract. J Gastroenterol Hepatol, 2009. 24(4): p. 537-46.

3,4,5-trimethoxybenzoic acid [2-(dimethylamino)-2-phenylbutyl] ester is a trihydroxybenzoic acid.
Trimebutine is a spasmolytic agent that regulates intestinal and colonic motility and relieves abdominal pain with antimuscarinic and weak mu opioid agonist effects. It is marketed for the treatment of irritable bowel syndrome (IBS) and lower gastrointestinal tract motility disorders, with IBS being one of the most common multifactorial GI disorders. It is used to restore normal bowel function and is commonly present in pharmaceutical mixtures as trimebutine maleate salt form. Trimebutine is not a FDA-approved drug, but it is available in Canada and several other international countries.
Proposed spasmolytic with possible local anesthetic action used in gastrointestinal disorders.

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Drug Indication
Indicated for symptomatic treatment of irritable bowel syndrome (IBS) and treatment of postoperative paralytic ileus following abdominal surgery.

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Mechanism of Action
At high concentrations, trimebutine is shown to inhibit the extracellular Ca2+ influx in the smooth muscle cells through voltage dependent L-type Ca2+ channels and further Ca2+ release from intracellular Ca2+ stores. Trimebutine is suggested to bind to the inactivated state of the calcium channel with high affinity. Reduced calcium influx attenuates membrane depolarization and decrease colon peristalsis. It also inhibits outward K+ currents in response to membrane depolarization of the GI smooth muscle cells at resting conditions through inhibition of delayed rectifier K+ channels and Ca2+ dependent K+ channels, which results in induced muscle contractions. Trimebutine binds to mu opioid receptors with more selectivity compared to delta or kappa opioid receptors but with lower affinity than their natural ligands. Its metabolites (N-monodesmethyl-trimebutine or nor-trimebutine), are also shown to bind to opoid receptors on brain membranes and myenteric synaptosomes.

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Trimebutine is a drug with gastrointestinal motility regulation, antispasmodic, and mild analgesic effects, acting through multiple targets (opioid receptors, calcium channels) [1][2][3]
Its gastrointestinal regulation mechanism includes activating gastrointestinal opioid receptors and inhibiting calcium influx, thereby regulating smooth muscle contraction and improving gastrointestinal motility disorders [2]
The analgesic effect is mainly mediated by central and peripheral opioid receptors, with more significant effect on visceral pain and no obvious addiction risk [1]
Clinical indications include functional dyspepsia, irritable bowel syndrome, postoperative gastrointestinal dysfunction, etc., especially suitable for gastrointestinal diseases related to abnormal gastrointestinal motility [3]
The administration route is mainly oral, and intramuscular injection is also available. The recommended dose is 300 mg daily for adults, divided into 3 doses, and 5 mg/kg/day for children, divided into 3 doses [3]

C22H29NO5

387.47

387.204

39133-31-8

Trimebutine maleate; 34140-59-5; Trimebutine-d5 fumarate; 2747915-18-8

5573

White to off-white solid powder

1.1±0.1 g/cm3

457.9±34.0 °C at 760 mmHg

79ºC

230.8±25.7 °C

0.0±1.1 mmHg at 25°C

1.534

4.34

57.23

0

6

10

28

466

0

LORDFXWUHHSAQU-UHFFFAOYSA-N

InChI=1S/C22H29NO5/c1-7-22(23(2)3,17-11-9-8-10-12-17)15-28-21(24)16-13-18(25-4)20(27-6)19(14-16)26-5/h8-14H,7,15H2,1-6H3

[2-(dimethylamino)-2-phenylbutyl] 3,4,5-trimethoxybenzoate

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)

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));
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;
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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;
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