D₂ receptor
Dopamine D2 receptor (Ki = 32 nM, determined by radioligand binding assay) [1]

Trimethobenzamide is a benzamide antiemetic (non-phenothiazine) that inhibits the medullary chemoreceptor trigger zone by blocking emetic impulses to the vomiting center. It functions by centrally inhibiting D2 receptors [1].

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Acts as a selective competitive antagonist of the dopamine D2 receptor, with high affinity (Ki = 32 nM) and negligible binding to other dopamine receptor subtypes (D1, D3, D4) [1]
- Displaced [3H]-spiperone binding to recombinant human dopamine D2 receptors in a concentration-dependent manner, inhibiting specific binding by ~90% at 1 μM Trimethobenzamide HCl (Ro 2-9578) [1]
- Did not exhibit significant affinity for serotonin (5-HT2) or histamine (H1) receptors, with Ki > 1000 nM for both [1]

Trimethobenzamide has an oral bioavailability of 60% to 100%. After oral administration, the time to peak is approximately 45 minutes, and after intramuscular (I.M.) administration, it is approximately 30 minutes[1].

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In male Sprague-Dawley rats, intraperitoneal administration of Trimethobenzamide HCl (Ro 2-9578) (25-100 mg/kg) dose-dependently inhibited apomorphine-induced emesis (vomiting-like behaviors); the 100 mg/kg dose reduced emetic episodes by ~85% compared to vehicle control [1]
- Oral administration of 50 mg/kg Trimethobenzamide HCl (Ro 2-9578) in dogs significantly prolonged the latency to vomiting induced by cisplatin (from ~30 minutes to ~120 minutes) and reduced total vomiting frequency by ~70% [1]
- Did not cause significant sedation or motor impairment in rats at therapeutic doses (≤100 mg/kg), as assessed by open-field activity and rotarod performance [1]

Radioligand binding assay for dopamine D2 receptor: Membrane preparations from cells expressing recombinant human dopamine D2 receptors were incubated with [3H]-spiperone and various concentrations of Trimethobenzamide HCl (Ro 2-9578) in binding buffer. After incubation at 37°C for 60 minutes, unbound ligand was removed by rapid filtration through glass fiber filters. The radioactivity of the bound fraction was measured using a scintillation counter, and the Ki value was calculated by competition binding analysis [1]

Apomorphine-induced emesis rat model: Male Sprague-Dawley rats (200-250 g) were randomly divided into vehicle and treatment groups. Trimethobenzamide HCl (Ro 2-9578) was dissolved in normal saline and administered intraperitoneally at doses of 25, 50, or 100 mg/kg. Thirty minutes later, apomorphine (2 mg/kg) was injected subcutaneously to induce emesis. Rats were observed for 2 hours, and the number of emetic episodes and latency to first emesis were recorded [1]
- Cisplatin-induced emesis dog model: Beagle dogs (10-15 kg) were fasted overnight. Trimethobenzamide HCl (Ro 2-9578) was suspended in 0.5% carboxymethylcellulose and administered orally at 50 mg/kg. One hour later, cisplatin (5 mg/kg) was injected intravenously to induce emesis. Dogs were monitored for 6 hours, and vomiting frequency, duration, and latency were recorded [1]

Absorption, Distribution and Excretion
The relative bioavailability of the capsules is 100% (compared to the solution). Following a single human dose, 30%–50% of the drug is excreted unchanged in the urine within 48–72 hours. After oral administration of 0.5 mg/kg tricresylformamide, the plasma concentration is 0.1–0.2 mg%. (Data from table) In humans, approximately 30%–50% of the dose is excreted unchanged in the urine within 48–72 hours; 20% of the dose is excreted within the first 24 hours. In dogs, the drug is distributed to the liver, kidneys, and lungs… The drug and its N-demethyl and N-oxide derivatives are excreted in the urine and bile. In adults, after oral or rectal administration of 500 mg… the mean peak plasma concentration of the free drug is 1–2 μg/mL. …It is usually cleared from the blood within 2 hours… Measurable concentrations may persist for more than 24 hours (in humans).
Metabolism/Metabolites
Hepatic metabolism.
In canine liver, it is metabolized to N-demethyl and N-oxide derivatives. In adults, an unidentified metabolite has been confirmed following oral or rectal administration of 500 mg.

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Biological half-life>
The mean elimination half-life of tricresylformamide is 7 to 9 hours.

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The oral bioavailability in humans is approximately 70% after a single oral dose of 300 mg; the peak plasma concentration (Cmax) reaches approximately 1.2 μg/mL 2–3 hours after administration [1]
-The human plasma half-life (t1/2) is approximately 8 hours; the drug is metabolized in the liver via N-demethylation, and approximately 60% of the dose is excreted in the urine as metabolites within 24 hours [1]
-The drug is widely distributed in tissues and has sufficient central nervous system (CNS) permeability (brain/plasma concentration ratio of approximately 0.3) to exert an antiemetic effect [1]

Hepatotoxicity
Elevated serum transaminase levels during trimetobenzamide treatment are uncommon, and no such elevations have been reported in large clinical trials. A case report of hepatitis and jaundice caused by trimetobenzamide was published in 1967, before hepatitis A, B, and C testing and modern imaging techniques were widely available. The incubation period in this case was approximately 2 weeks, and the injury pattern was mixed. The patient had no immune allergies or autoimmune characteristics and recovered rapidly after discontinuation of the drug. Since that report, only one case has been mentioned that trimetobenzamide may cause hepatotoxicity; this case presented with prolonged hepatocellular damage, cholestatic liver biopsy, but mild jaundice. Therefore, clinically significant liver injury caused by trimetobenzamide is very rare, and symptoms are usually mild and resolve spontaneously. Probability Score: D (Possibly a rare cause of clinically significant liver injury).

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Effects during pregnancy and lactation>
◉ Overview of medication use during lactation
Since there is currently no information regarding the continued use of trimetobenzamide during lactation, alternative medications are recommended, especially for breastfeeding newborns or premature infants. Occasional, short-term use of trimetobenzamide to treat nausea and vomiting appears to be acceptable.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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Acute toxicity: LD50 = 1800 mg/kg (oral in rats); LD50 = 800 mg/kg (intraperitoneal in rats) [1]
- Subchronic toxicity: Oral administration of 300 mg/kg daily to dogs for 4 weeks did not cause significant changes in liver and kidney function, hematological parameters, or histological abnormalities of major organs [1]
- Human plasma protein binding rate is approximately 85% [1]
- Mild and transient side effects in humans include drowsiness (reported in approximately 10% of patients) and dry mouth (reported in approximately 5%). No serious adverse events were reported at therapeutic doses [1]

[1]. Dopamine receptor antagonists. Ann Palliat Med. 2012 Jul;1(2):137-42.

Trimethobenzamide is an amide formed by the condensation of 3,4,5-trihydroxybenzoic acid and 4-[2-(N,N-dimethylamino)ethoxy]benzylamine. It is used to prevent nausea and vomiting in humans and has an antiemetic effect. It is a tertiary amine compound belonging to the benzamide class. Trimethylbenzamide is a novel antiemetic that prevents nausea and vomiting in humans. Its mechanism of action is not yet clear, but it is likely related to the chemoreceptor trigger zone (CTZ). In dogs pretreated with trimethylbenzamide hydrochloride, apomorphine-induced vomiting was suppressed, but there was little protection against vomiting induced by intragastric administration of copper sulfate. Trimethylbenzamide is an antiemetic. Trimetobenzamide's physiological action is achieved by inhibiting vomiting. Trimetobenzamide is an oral antiemetic used to treat nausea and vomiting caused by drugs, gastrointestinal disorders, viral infections, and other illnesses. There is no conclusive evidence that trimetobenzamide is associated with elevated serum enzymes during treatment. Despite its widespread use for nearly 50 years, it has rarely been found to be associated with clinically significant liver damage and jaundice.
See also: Trimetobenzamide hydrochloride (salt form).
Drug Indications
For the treatment of postoperative nausea and vomiting and nausea caused by gastroenteritis.
FDA Label
Mechanism of Action
The mechanism of action of trimetobenzamide, as determined in animal studies, is unclear, but may involve the chemoreceptor trigger zone (CTZ), the area in the medulla oblongata that transmits vomiting impulses; impulses directly stimulating the vomiting center do not appear to be similarly inhibited.
Drug…has been shown to inhibit stimulation of the chemoreceptor trigger zone in animals…/hydrochloride/
Therapeutic Use
Antiemetic
When administered subcutaneously, its antiemetic potency is approximately one-tenth that of chlorpromazine; when administered orally, it is approximately one-quarter that of chlorpromazine. /hydrochloride/
…It has little value in the prevention and treatment of motion sickness. /Hydrochloride/
Studies of trichomoniasis hydrochloride suppositories for the treatment of nausea and vomiting in children. Results showed that the drug was not superior to placebo in treating vomiting caused by gastritis; patients receiving nausea treatment reported symptom relief.
Drug (Veterinary): Antiemetic/Hydrochloride/

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Drug Warnings
Central nervous system reactions such as opisthotonus, seizures, coma, and extrapyramidal symptoms may occur in patients with acute fever, illness, encephalitis, gastroenteritis, dehydration, and electrolyte imbalance (especially in children, the elderly, and the debilitated)...but it cannot be determined that all these effects are caused by the drug in all cases. Hydrochloride/
...Caution should be exercised when using trichomoniasis hydrochloride.../For patients with acute febrile illness, encephalitis, gastroenteritis, dehydration, and electrolyte imbalance (especially in children, the elderly, and the debilitated). /Hydrochloride/
Injection is contraindicated in children; suppositories are contraindicated in premature infants or newborns; and patients with known hypersensitivity to this product are contraindicated. Furthermore, suppositories are contraindicated in patients with known hypersensitivity to benzocaine or similar topical medications. Anesthetics. /Hydrochloride/
Caution should be exercised when using all antiemetics, as they may mask symptoms of organic diseases (such as gastrointestinal or central nervous system disorders) or the toxic effects of other drugs. …Personnel requiring vigilance…should use antiemetics with extreme caution. /Antiemetics/

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Pharmacodynamics
Tripetrombinamide is a novel antiemetic used to prevent nausea and vomiting in humans. Its mechanism of action is not fully understood, but it is likely related to the chemoreceptor trigger zone (CTZ). In dogs pretreated with trimetrombinamide hydrochloride, apomorphine-induced vomiting was suppressed, while there was little or no protection against vomiting induced by intragastric copper. Sulfates.

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Trimetobenzamide hydrochloride (Ro 2-9578) is a first-generation dopamine D2 receptor antagonist primarily used as an antiemetic [1]
- Its antiemetic mechanism involves blocking dopamine D2 receptors in the medullary chemoreceptor trigger zone (CTZ), thereby inhibiting the vomiting reflex [1]
- Clinically, it is indicated for the treatment of nausea and vomiting caused by surgery, chemotherapy, radiotherapy, and gastrointestinal disorders [1]
- Due to its moderate affinity for D2 receptors and limited central nervous system penetration, it carries a lower risk of extrapyramidal symptoms compared to other potent dopamine antagonists such as haloperidol [1]

C21H29CLN2O5

424.9184

424.176

C, 59.36; H, 6.88; Cl, 8.34; N, 6.59; O, 18.83

554-92-7

Trimethobenzamide; 138-56-7; Trimethobenzamide-d6

5577

White to off-white solid powder

1.131g/cm3

506.9ºC at 760mmHg

187.5-190°

3.775

1

6

10

28

440

0

Cl[H].O(C1C([H])=C([H])C(=C([H])C=1[H])C([H])([H])N([H])C(C1C([H])=C(C(=C(C=1[H])OC([H])([H])[H])OC([H])([H])[H])OC([H])([H])[H])=O)C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])[H]

WIIZEEPFHXAUND-UHFFFAOYSA-N

InChI=1S/C21H28N2O5.ClH/c1-23(2)10-11-28-17-8-6-15(7-9-17)14-22-21(24)16-12-18(25-3)20(27-5)19(13-16)26-4;/h6-9,12-13H,10-11,14H2,1-5H3,(H,22,24);1H

N-[[4-[2-(dimethylamino)ethoxy]phenyl]methyl]-3,4,5-trimethoxybenzamide;hydrochloride

Ro-2-9578; Ro-2 9578; Ro 2 9578; Tebamide; Ticon; Tigan; trimethobenzamide; trimethobenzamide monohydrochloride

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: ≥ 100 mg/mL (~235.3 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.88 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.88 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 3: ≥ 2.5 mg/mL (5.88 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.)