D2 receptor[1]

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

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

Absorption, Distribution and Excretion
The relative bioavailability of capsules is 100% compared to solutions. Following a single human dose, 30% to 50% of the drug is excreted unchanged in the urine within 48 to 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% to 50% of the dose is excreted unchanged in the urine within 48 to 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. After oral or rectal administration of 500 mg in adults… 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.

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Metabolism/Metabolites
Hepatic metabolism.
In canine liver, it is metabolized to N-demethyl and N-oxide derivatives. …In adults, after oral or rectal administration of 500 mg…an unidentified metabolite has been identified.

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

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 two 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 as potentially causing hepatotoxicity with trimetobenzamide. 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 no information regarding the continued use of trimetobenzamide during lactation, it is recommended to prioritize other medications, especially when 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.

[1]. Smith HS, et al. 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. Trimethobenzamide 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 Trimethobenzamide hydrochloride, apomorphine-induced vomiting was suppressed, but there was little protection against vomiting induced by intragastric administration of copper sulfate. Trimethobenzamide 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 trimetrombin hydrochloride, apomorphine-induced vomiting was suppressed, but there was little protection against vomiting induced by intragastric administration of copper sulfate.

C21H28N2O5

388.45742

388.2

138-56-7

Trimethobenzamide hydrochloride;554-92-7;Trimethobenzamide-d6

5577

Typically exists as solid at room temperature

1.131 g/cm3

506.9ºC at 760 mmHg

260.4ºC

2.13E-10mmHg at 25°C

2.973

1

6

10

28

440

0

CN(CCOC1=CC=C(CNC(C2=CC(OC)=C(OC)C(OC)=C2)=O)C=C1)C

FEZBIKUBAYAZIU-UHFFFAOYSA-N

InChI=1S/C21H28N2O5/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)

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

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

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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