Trimebutine

Overview

Trimebutine is a drug which is used in the treatment of irritable bowel syndrome and other gastrointestinal disorders. It is sometimes combined with simethicone as a combination drug. Trimebutine is formulated as a tablet or granules for oral suspension.[1][2][3] WP

Uses, dosage and effects

Medical uses

Trimebutine is used in the treatment of irritable bowel syndrome (IBS) and other gastrointestinal disorders. WP

Risks and side effects

Side effects

Trimebutine may cause following side effects:[4] WP

• Psychiatric disturbances: anxiety[4] WP
• CNS reactions: somnolence, malaise, vertigo, paresthesia, headache, apathy[4] WP
• Ear problems: hearing loss[4] WP
• Heart problems: tachycardia[4] WP
• GI reactions: xerostomia, taste disorders, diarrhoea, dyspepsia, upper quadrant pain, lip paresthesia, nausea, vomiting, constipation, excessive thirst[4] WP
• Hepatic and bile ducts reactions: hepatic insufficiency, hepatitis, increased liver enzymes[4] WP
• Skin and soft tissue reactions: rash, pruritus, urticaria, flushing, blistering, lumps, exudation, erythema multiforme[4] WP
• Renal reactions: urinary retention[4] WP
• Reproductive system reactions: dysmenorrhoea, mastitis, gynecomastia in males, breast pain[4] WP

Carcinogenicity

According to European Medicines Agency, formulations of trimebutine might be contaminated with N-nitrosamines. However, it was assigned CPCA Category 5 with acceptable daily intake of 1500 ng/day.[5] WP

Interactions

Interactions

Trimebutine can increase the length of anaesthesia induced with d-tubocurarine. Other interactions include:[4][6] WP

• Potentiation of anticholinergic effects caused by zotepine[4][6] WP
• Decreasing efficacy of cisapride[4][6] WP
• Procainamide (potentiation of vagus nerve activity inhibition, thereby causing a positive chronotropic effect and, in turn, tachycardia)[4][6] WP
• calcium channel blockers[4][6] WP

Pharmacology

Pharmacodynamics

Trimebutine is a multimodal drug that acts on many receptors in the body. Its main effects are mediated through inhibition of voltage-gated L-type calcium channels, thereby decreasing calcium influx in smooth muscle in the gut. This mechanism explains its ability to slow peristalsis, which in turn helps with diarrhoea management in IBS patients. Antispasmodic effect is mediated through inhibition of inward rectifier potassium channels and calcium-dependend potassium channels. Moreover, trimebutine and its metabolite N-desmethyltrimebutine exert non-selective antagonistic effect on muscarinic acetylcholine receptors, which is believed to potentiate its antispasmodic effects, as do many other drugs in this class.[6–9] WP

Moreover, trimebutine and N-desmethyltrimebutine act as weak agonists of opioid receptors, specifically μ-, δ-, and κ-opioid receptor subtypes throughout the gut, which was shown in animal-model studies. Trimebutine exerts its effects in part due to causing a premature activation of phase III of the migrating motor complex in the digestive tract. This mode of action explains trimebutine's ability to mediate gastrointestinal motility in different parts of the gastrointestinal tract, both stimulating and inhibiting spontaneous contractions.[10][11] WP

In vitro, trimebutine also exhibits antagonistic effects in sodium channels with IC₅₀ equal 8.4 μM and inhibits glutamate release.[3] WP

Absorption and distribution

Oral bioavailability of trimebutine is nearly 100% for the maleate salt. Maximum serum concentration (Cₘₐₓ) is achieved after 30 minutes for 100 mg dose and 0.88 h for 200 mg dose. The level of serum albumin binding is minimal. Half-life (t1/2) of 200 mg timebutine maleate is equal to 2.77 h.[4][6] WP

Metabolism and excretion

Trimebutine exhibits first-pass metabolism effect, which in turn generates N-desmethyltrimebutine (nortrimebutine). Predominantly, trimebutine is excreted in urine, mainly as 2-dimethylamino-2-phenylbutan-1-ol, whereas fecal excretion is minimal (5-12%). Additionally, trimebutine might be metabolised through glucuronidation.[6][12] WP

Research

Research

Trimebutine is investigated for the treatment of functional dyspepsia-IBS overlap syndrome, post-operative nausea and vomiting. A clinical trial evaluating trimebutine as an adjunctive treatment to rabeprazole-resistant reflux oesophageitis was withdrawn due to lack of funds.[13][14][15] WP

Novel salts of trimebutine

Wallace et al. synthesised several new salts with improved analgesic properties in patients with irritable bowel syndrome. These include:[16] WP

• Trimebutine nitroarginate and derivatives – arginine nitro-derivative acts as a nitric oxide donor, which exerts anti-inflammatory effect (similarly to naproxcinod)[17][18] WP
• Trimebutine thiocarbamoylbenzoate – thioamide group acts as a hydrogen sulfide donor, also acting as an anti-inflammatory and analgesic agent[19] WP

Acute ulcerative colitis

Trimebutine maleate encapsulated by nanostructured lipid carriers was shown to induce protective effects on colon mucosa in acetic-acid colitis in rats.[20] WP

Cancer

Heejin et al. showed that trimebutine is effective at stopping ovarian cancer cells from growing in vitro. This effect is believed to be exerted through G0/G1 phase switch arrest, voltage-gated calcium channels and calcium-activated potassium channels inhibition and suppressing Wnt, Notch and Hedgehog pathways.[21] WP

Yi-pu Fan et al. found that trimebutine can inhibit glioma and glioblastoma cells from proliferating by promoting apoptosis and downregulation of Bcl-2, thereby upregulating Bax pro-apoptotic factor.[22] WP

Alkaline corneal burns

Hitoshi et al. showed that trimebutine can inhibit inflammation in corneal burns caused by alkali. This protective activity is thought to be mediated by high-mobility group box 1-receptor inhibitor, which causes decreased macrophage and neutrophil infiltration.[23] WP

Legal status

Brand names

The maleic acid salt of trimebutine is marketed under the trademarks of Antinime, Cineprac, Colospasmyl, Colypan, Crolipsa, Debricol, Debridat, Debretin, Digedrat, Espabion, Gast Reg, Ircolon, Irritratil, Krisxon, Muttifen, Neotina, Polybutin, Sangalina, Trebutel, Tribudat, Tributina, Tribux, Trim, Trimeb, Trimedat, and Trimedine. Combination with medazepam appears to have been marketed.[24] WP

Chemistry

Formula

C22H29NO5 PC

Molar mass (g/mol)

387.5 PC

IUPAC name (computed by PubChem)

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

SMILES

CCC(COC(=O)C1=CC(=C(C(=C1)OC)OC)OC)(C2=CC=CC=C2)N(C)C PC

InChIKey

LORDFXWUHHSAQU-UHFFFAOYSA-N PC

PubChem CID

5573

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

1. Journal / agency Kaneto H, Takahashi M, Watanabe J. The opioid receptor selectivity for trimebutine in isolated tissues experiments and receptor binding studies. Journal of Pharmacobio-Dynamics. July 1990. doi:10.1248/bpb1978.13.448 · PMID 1963196
2. Other Libertrim SII. 17 February 2025
3. Other Debridat, 7,87 mg/g, granulat do sporządzania zawiesiny doustnej. Charakterystyka Produktu Leczniczego. 11 July 1996
4. Other 100 mg, tabletki. Charakterystyka Produktu Leczniczego
5. Journal / agency Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products. 19 July 2024
6. Other Trimebutine Maleate Tablets 100 mg and 200 mg. Lower gastrointestinal tract motility regulator. 1 July 2010
7. Journal / agency Lee HT, Kim BJ. Trimebutine as a modulator of gastrointestinal motility. Archives of Pharmacal Research. June 2011. doi:10.1007/s12272-011-0600-7 · PMID 21725804
8. Journal / agency Nagasaki M, Komori S, Ohashi H. Effect of trimebutine on voltage-activated calcium current in rabbit ileal smooth muscle cells. British Journal of Pharmacology. September 1993. doi:10.1111/j.1476-5381.1993.tb13823.x · PMID 8220900 · PMC2176005
9. Journal / agency Tan W, Zhang H, Luo HS, Xia H. Effects of trimebutine maleate on colonic motility through Ca²+-activated K+ channels and L-type Ca²+ channels. Archives of Pharmacal Research. June 2011. doi:10.1007/s12272-011-0615-0 · PMID 21725819
10. Journal / agency Hiyama T, Yoshihara M, Tanaka S, Haruma K, Chayama K. Effectiveness of prokinetic agents against diseases external to the gastrointestinal tract. Journal of Gastroenterology and Hepatology. April 2009. doi:10.1111/j.1440-1746.2009.05780.x · PMID 19220673
11. Journal / agency Pascaud X, Petoux F, Roman F, Vauche D, Junien JL. Mode of action of trimebutine: involvement if opioid receptors. Presse Médicale. February 1989. PMID 2537972
12. Journal / agency Miura Y, Chishima S, Takeyama S. Studies of metabolic pathways of trimebutine by simultaneous administration of trimebutine and its deuterium-labeled metabolite. Drug Metabolism and Disposition: The Biological Fate of Chemicals. 1989. doi:10.1016/S0090-9556(25)07655-X · PMID 2571489
13. Journal / agency Hussain Z, Jung DH, Lee YJ, Park H. The Effect of Trimebutine on the Overlap Syndrome Model of Guinea Pigs. Journal of Neurogastroenterology and Motility. October 2018. doi:10.5056/jnm18049 · PMID 30114898 · PMC6175557
14. Other Lhee SH. Trimebutine Maleate (NEWBUTIN SR 300 mg Tab) as a Prophylactic Anti-emetic Drug for Patients Who Underwent Arthroscopic Rotator Cuff Repair: a Randomized Controlled Study. 2013-11-08
15. Other Shi Y. The Clinical Efficacy and Safety of Trimebutine Maleate Combined With Rabeprazole in Patients With Grade A or B Reflux Esophagitis Whose Symptoms Refractory to Rabeprazole. 2023-01-30
16. Other Salts of Trimebutine and N-Desmethyl Trimebutine
17. Journal / agency Iwata M, Inoue T, Asai Y, Hori K, Fujiwara M, Matsuo S, Tsuchida W, Suzuki S. The protective role of localized nitric oxide production during inflammation may be mediated by the heme oxygenase-1/carbon monoxide pathway. Biochemistry and Biophysics Reports. September 2020. doi:10.1016/j.bbrep.2020.100790 · PMID 32760814 · PMC7390790
18. Journal / agency Wallace JL. Nitric oxide as a regulator of inflammatory processes. Memórias do Instituto Oswaldo Cruz. March 2005. doi:10.1590/S0074-02762005000900002 · PMID 15962091
19. Journal / agency Gemici B, Wallace JL. Hydrogen Sulfide in Redox Biology, Part B. January 2015. doi:10.1016/bs.mie.2014.11.034 · PMID 25747480
20. Journal / agency Motawea A, Abd El Hady WE, Ahmed El-Emam G. The protective impact of adapted trimebutine maleate-loaded nanostructured lipid carriers for alleviating the severity of acute colitis. Drug Delivery. December 2022. doi:10.1080/10717544.2022.2050847 · PMID 35297699 · PMC8933020
21. Journal / agency Lee H, Kwon OB, Lee JE, Jeon YH, Lee DS, Min SH, Kim JW. Repositioning Trimebutine Maleate as a Cancer Treatment Targeting Ovarian Cancer Stem Cells. Cells. April 2021. doi:10.3390/cells10040918 · PMID 33923707 · PMC8072797
22. Journal / agency Fan YP, Liu P, Xue WK, Zhao WJ, Pan HC. Trimebutine Promotes Glioma Cell Apoptosis as a Potential Anti-tumor Agent. Frontiers in Pharmacology. 2018-06-21. doi:10.3389/fphar.2018.00664 · PMID 29977208 · PMC6021541
23. Journal / agency Goto H, Arima T, Takahashi A, Tobita Y, Nakano Y, Toda E, Shimizu A, Okamoto F. Trimebutine prevents corneal inflammation in a rat alkali burn model. Scientific Reports. May 2024. doi:10.1038/s41598-024-61112-4 · PMID 38802470 · PMC11130283
24. Journal / agency Jhee OH, Lee YS, Shaw LM, Jeon YC, Lee MH, Lee SH, Kang JS. Pharmacokinetic and bioequivalence evaluation of two formulations of 100 mg trimebutine maleate (Recutin and Polybutin) in healthy male volunteers using the LC-MS/MS method. Clinica Chimica Acta; International Journal of Clinical Chemistry. January 2007. doi:10.1016/j.cca.2006.06.006 · PMID 16854404

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