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Trimethobenzamide (also known as Ro 2-9578; trade names Tebamide, Tigan), a blocker of the D2 receptor, is a potent antiemetic that is used to prevent nausea and vomiting. Patients with gastroenteritis, medication-induced nausea, and other ailments are frequently prescribed it. Because it doesn't affect the histaminergic, dopaminergic, or serotonergic systems, trimethobenzamide is widely regarded as the most effective antiemetic and is less likely to have unwanted side effects. It needs a prescription in the United States. While the precise mode of action of trimethobenzamide remains unclear, it is thought to impact the medulla oblongata's chemoreceptor trigger zone (CTZ).
Physicochemical Properties
| Molecular Formula | C21H29CLN2O5 |
| Molecular Weight | 424.9184 |
| Exact Mass | 424.176 |
| Elemental Analysis | C, 59.36; H, 6.88; Cl, 8.34; N, 6.59; O, 18.83 |
| CAS # | 554-92-7 |
| Related CAS # | Trimethobenzamide; 138-56-7; Trimethobenzamide-d6 |
| PubChem CID | 5577 |
| Appearance | White to off-white solid powder |
| Density | 1.131g/cm3 |
| Boiling Point | 506.9ºC at 760mmHg |
| Melting Point | 187.5-190° |
| LogP | 3.775 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 6 |
| Rotatable Bond Count | 10 |
| Heavy Atom Count | 28 |
| Complexity | 440 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | 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] |
| InChi Key | WIIZEEPFHXAUND-UHFFFAOYSA-N |
| InChi Code | 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 |
| Chemical Name | N-[[4-[2-(dimethylamino)ethoxy]phenyl]methyl]-3,4,5-trimethoxybenzamide;hydrochloride |
| Synonyms | Ro-2-9578; Ro-2 9578; Ro 2 9578; Tebamide; Ticon; Tigan; trimethobenzamide; trimethobenzamide monohydrochloride |
| HS Tariff Code | 2934.99.9001 |
| Storage |
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. |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | D2 receptor |
| ln Vitro | 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]. |
| ln Vivo | 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]. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion The relative bioavailability of the capsule formulation compared to the solution is 100%. Between 30 – 50% of a single dose in humans is excreted unchanged in the urine within 48–72 hours. CONCN IN BLOOD WAS 0.1-0.2 MG% AFTER ORAL ADMIN OF 0.5 MG/KG OF TRIMETHOBENZAMIDE. /FROM TABLE/ IN MAN, APPROX 30 TO 50% OF...DOSE IS EXCRETED IN URINE AS INTACT DRUG WITHIN 48 TO 72 HR; 20% OF...DOSE IS EXCRETED DURING FIRST 24 HR. IN DOGS, /DRUG/ IS DISTRIBUTED IN LIVER, KIDNEY AND LUNG...DRUG & /N-DESMETHYL & N-OXIDE DERIV/ EXCRETED IN URINE AND BILE IN ADULTS, FOLLOWING ORAL OR RECTAL ADMIN OF 500 MG...AVG PEAK BLOOD LEVELS OF FREE DRUG /WERE 1-2 MCG/ML/. ...GENERALLY CLEARED FROM THE BLOOD WITHIN 2 HR...MEASURABLE CONCN MAY PERSIST FOR OVER 24 HR /HUMAN/ Metabolism / Metabolites Hepatic. METABOLIZED IN THE LIVER OF THE DOG TO THE N-DESMETHYL AND N-OXIDE DERIVATIVES. ...IN /HUMAN/ ADULTS, FOLLOWING ORAL OR RECTAL ADMIN OF 500 MG...AN UNIDENTIFIED METABOLITE HAS BEEN DEMONSTRATED. Biological Half-Life The mean elimination half-life of trimethobenzamide is 7 to 9 hours. |
| Toxicity/Toxicokinetics |
Hepatotoxicity Serum aminotransferase elevations during trimethobenzamide therapy are uncommon and rates of such elevations have not been reported in large clinical trials. A single case report of hepatitis and jaundice attributed to trimethobenzamide was published in 1967 that predated availability of tests for hepatitis A, B and C and of modern imaging studies. The latency to onset was approximately 2 weeks and the pattern of injury was mixed. There were no immunoallergic or autoimmune features and recovery was prompt once the medication was stopped. Since that report, there has only been a single mention of possible hepatotoxicity due to trimethobenzamide, a somewhat prolonged case of hepatocellular injury with a cholestatic pattern on liver biopsy despite minimal jaundice. Thus, clinically apparent liver injury from trimethobenzamide must be very rare and is generally mild and self-limited in course. Likelihood score: D (possible rare cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Because no information is available on the continuous use of trimethobenzamide during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. Occasional, short-term use of trimethobenzamide for the treatment of nausea and vomiting appears to be acceptable. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. |
| References |
[1]. Dopamine receptor antagonists. Ann Palliat Med. 2012 Jul;1(2):137-42. |
| Additional Infomation |
Trimethobenzamide is the amide obtained by formal condensation of 3,4,5-trihydroxybenzoic acid with 4-[2-(N,N-dimethylamino)ethoxy]benzylamine. It is used to prevent nausea and vomitting in humans. It has a role as an antiemetic. It is a tertiary amino compound and a member of benzamides. Trimethobenzamide is a novel antiemetic which prevents nausea and vomiting in humans. Its actions are unclear but most likely involves the chemoreceptor trigger zone (CTZ). In dogs pretreated with trimethobenzamide HCl, the emetic response to apomorphine is inhibited, while little or no protection is afforded against emesis induced by intragastric copper sulfate. Trimethobenzamide is an Antiemetic. The physiologic effect of trimethobenzamide is by means of Emesis Suppression. Trimethobenzamide is an orally available, antiemetic agent used in the therapy of nausea and vomiting associated with medications and gastrointestinal, viral and other illnesses. Trimethobenzamide has not been linked convincingly to elevations in serum enzymes during therapy and despite widescale use for almost 50 years, it has rarely been linked to instances of clinically apparent liver injury with jaundice. See also: Trimethobenzamide Hydrochloride (has salt form). Drug Indication For the treatment of postoperative nausea and vomiting and for nausea associated with gastroenteritis. FDA Label Mechanism of Action The mechanism of action of trimethobenzamide as determined in animals is obscure, but may involve the chemoreceptor trigger zone (CTZ), an area in the medulla oblongata through which emetic impulses are conveyed to the vomiting center; direct impulses to the vomiting center apparently are not similarly inhibited. DRUG...SHOWN TO INHIBIT STIMULI @ CHEMORECEPTOR TRIGGER ZONE IN ANIMALS... /HYDROCHLORIDE SALT/ Therapeutic Uses Antiemetics ITS ANTIEMETIC POTENCY IS ABOUT ONE-TENTH THAT OF CHLORPROMAZINE WHEN GIVEN SC & ONE-FOURTH THAT OF LATTER WHEN GIVEN ORALLY. /HYDROCHLORIDE SALT/ ...HAS LITTLE OR NO VALUE IN PREVENTION & TREATMENT OF MOTION SICKNESS. /HYDROCHLORIDE SALT/ STUDY OF TRIMETHOBENZAMIDE HYDROCHLORIDE SUPPOSITORIES IN TREATMENT OF NAUSEA & VOMITING IN CHILDREN. RESULTS INDICATE THAT THEY ARE NO MORE EFFECTIVE THAN PLACEBO FOR TREATMENT OF VOMITING ASSOC WITH GASTRITIS, PT TREATED FOR NAUSEA REPORTED RELIEF. MEDICATION (VET): ANTIEMETIC /HYDROCHLORIDE SALT/ Drug Warnings IN PT WITH ACUTE FEBRILE, ILLNESS, ENCEPHALITIDES, GASTROENTERITIS, DEHYDRATION, & ELECTROLYTE IMBALANCE (ESP IN CHILDREN & ELDERLY & DEBILITATED) CNS REACTIONS SUCH AS OPISTHOTONOS, CONVULSIONS, COMA, & EXTRAPYRAMIDAL SYMPTOMS...BUT IT IS NOT CERTAIN THAT THESE EFFECTS WERE IN ALL CASES DUE TO...DRUG. /HYDROCHLORIDE SALT/ ...CAUTION SHOULD BE EXERCISED WHEN TRIMETHOBENZAMIDE HYDROCHLORIDE IS USED... /IN PT WITH ACUTE FEBRILE ILLNESS, ENCEPHALITIDES, GASTROENTERITIS, DEHYDRATION, & ELECTROLYTE IMBALANCE (ESP IN CHILDREN & ELDERLY & DEBILITATED/. /HYDROCHLORIDE SALT/ USE OF INJECTABLE FORM OF DRUG IN CHILDREN, SUPPOSITORIES IN PREMATURE OR NEWBORN INFANTS, & USE OF DRUG IN PT HYPERSENSITIVE TO IT ARE CONTRAINDICATED. ALSO, SUPPOSITORIES SHOULD NOT BE USED IN PT KNOWN TO BE SENSITIVE TO BENZOCAINE OR SIMILAR TYPES OF LOCAL ANESTHETICS. /HYDROCHLORIDE SALT/ CAUTION IS REQUIRED IN USE OF ALL ANTIEMETICS BECAUSE THEY MAY MASK SYMPTOMS OF ORGANIC DISEASE (EG, GI OR CNS DISORDERS) OR TOXIC EFFECTS OF OTHER DRUGS. ... INDIVIDUALS WHOSE ACTIVITIES REQUIRE ALERTNESS...SHOULD USE ANTIEMETICS WITH GREAT CAUTION. /ANTIEMETICS/ Pharmacodynamics Trimethobenzamide is a novel antiemetic which prevents nausea and vomiting in humans. Its actions are unclear but most likely involves the chemoreceptor trigger zone (CTZ). In dogs pretreated with trimethobenzamide HCl, the emetic response to apomorphine is inhibited, while little or no protection is afforded against emesis induced by intragastric copper sulfate. |
Solubility Data
| Solubility (In Vitro) | DMSO: ≥ 100 mg/mL (~235.3 mM) |
| Solubility (In Vivo) |
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. 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. 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3534 mL | 11.7669 mL | 23.5338 mL | |
| 5 mM | 0.4707 mL | 2.3534 mL | 4.7068 mL | |
| 10 mM | 0.2353 mL | 1.1767 mL | 2.3534 mL |