Chemistry:Trimebutine

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Trimebutine is a drug with antimuscarinic and very weak mu opioid agonist effects.[1] It is used for the treatment of irritable bowel syndrome and other gastrointestinal disorders. It is sometimes combined with simethicone as a combination drug.[2] Trimebutine is formulated as a tablet or granules for oral suspension.[3]

Pharmacology

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,[4][5] 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.[4][6] Moreover, trimebutine and its metabolite N-desmethyltrimebutine exert non-selective antagonistic effect on mAChRs, which is believed to potentiate its antispasmodic effects, as do many other drugs in this class.[7]

Moreover, trimebutine and N-desmethyltrimebutine act as weak agonists of opioid receptors, specifically mu, delta and kappa 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.[8] 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.[9]

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

Pharmacokinetics

Oral bioavailability of trimebutine is nearly 100% for the maleate salt. Maximum serum concentration (Cmax) is achieved after 30 minutes for 100 mg dose[10] and 0.88 h for 200 mg dose.[7] The level of serum albumin binding is minimal.[7] Half-life (t1/2) of 200 mg timebutine maleate is equal to 2.77 h.[7]

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%).[11] Additionally, trimebutine might be metabolised through glucuronidation.[7]

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.[12]

Interactions

Trimebutine can increase the length of anaesthesia induced with d-tubocurarine.[7][10] Other interactions include:[10]

Adverse effects

Trimebutine may cause following side-effects:[10]

Synthesis

Trimebutine can be synthesised from 1-phenylpropan-1-one (1). Firstly, it is converted to the corresponding oxirane through trimethylsulfoxonium idoide with sodium hydride in DMSO and THF, yielding 2-ethyl-2-phenyl-oxirane (2). Next, 2 undergoes ring-opening with dimethylaluminium N,N-dimethylamide in diethyl ether, yielding 2-(dimethylamino)-2-phenyl-butan-1-ol (4) and 2-phenylbutanal (3) as a byproduct. Then, 4 reacts with 3,4,5-trimethoxybenzoyl chloride (5) in triethylamine and THF, which is catalysed by 4-dimethylaminopyrridine (DMAP), yielding trimebutine.

Trimebutine synthesis[13]

Research

Trimebutine is investigated for the treatment of functional dyspepsia-IBS overlap syndrome,[14] post-operative nausea and vomiting.[15] A clinical trial evaluating trimebutine as an adjunctive treatment to rabeprazole-resistant reflux oesophageitis was withdrawn due to lack of funds.[16]

Novel salts of trimebutine

Wallace et al. synthesised several new salts with improved analgesic properties in patients with irritable bowel syndrome.[17] These include:

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.[21]

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.[22]

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.[23]

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.[24]

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,[25] Sangalina, Trebutel, Tribudat, Tributina, Tribux, Trim, Trimeb, Trimedat, and Trimedine. Combination with medazepam appears to have been marketed.[citation needed]

See also

References

  1. ↑ "The opioid receptor selectivity for trimebutine in isolated tissues experiments and receptor binding studies". Journal of Pharmacobio-dynamics 13 (7): 448–453. July 1990. doi:10.1248/bpb1978.13.448. PMID 1963196. 
  2. ↑ "Libertrim SII". 17 February 2025. https://www.medicamentosplm.com/Home/productos/libertrim.sii.comprimidos/35/101/10761/25#. 
  3. ↑ 3.0 3.1 "Debridat, 7,87 mg/g, granulat do sporządzania zawiesiny doustnej. Charakterystyka Produktu Leczniczego". 11 July 1996. https://rejestry.ezdrowie.gov.pl/medicinal-products/897/characteristic. 
  4. ↑ 4.0 4.1 "Trimebutine as a modulator of gastrointestinal motility". Archives of Pharmacal Research 34 (6): 861–864. June 2011. doi:10.1007/s12272-011-0600-7. PMID 21725804. 
  5. ↑ "Effect of trimebutine on voltage-activated calcium current in rabbit ileal smooth muscle cells". British Journal of Pharmacology 110 (1): 399–403. September 1993. doi:10.1111/j.1476-5381.1993.tb13823.x. PMID 8220900. 
  6. ↑ "Effects of trimebutine maleate on colonic motility through Ca²+-activated K+ channels and L-type Ca²+ channels". Archives of Pharmacal Research 34 (6): 979–985. June 2011. doi:10.1007/s12272-011-0615-0. PMID 21725819. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 "Trimebutine Maleate Tablets 100 mg and 200 mg. Lower gastrointestinal tract motility regulator". AA PHARMA Inc.. 1 July 2010. https://www.aapharma.ca/downloads/en/PIL/2016/Trimebutine-PM.pdf. 
  8. ↑ "Effectiveness of prokinetic agents against diseases external to the gastrointestinal tract". Journal of Gastroenterology and Hepatology 24 (4): 537–546. April 2009. doi:10.1111/j.1440-1746.2009.05780.x. PMID 19220673. 
  9. ↑ "[Mode of action of trimebutine: involvement if opioid receptors]". Presse Médicale (Paris, France) 18 (6): 298–302. February 1989. PMID 2537972. 
  10. ↑ 10.0 10.1 10.2 10.3 "100 mg, tabletki. Charakterystyka Produktu Leczniczego". Tribux Bio. https://www.biofarm.pl/fileadmin/user_upload/Tribux_Bio_-_ChPL.pdf. 
  11. ↑ "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 17 (4): 455–462. 1989. doi:10.1016/S0090-9556(25)07655-X. PMID 2571489. 
  12. ↑ "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". European Medicines Agency. 19 July 2024. https://www.ema.europa.eu/system/files/documents/opinion-on-any-scientific-matter/13th-niog_nitrosamines-emea-h-a5-3-1490-qa-art-5-3-revision-22-en.pdf. 
  13. ↑ "A short Synthesis of Trimebutine, 2-Dimethylamino-2-phenylbutyl3,4,5-trimethylbenzoate" (in en). Bulletin of the Korean Chemical Society 26 (2): 340–342. 2005-02-20. doi:10.5012/bkcs.2005.26.2.340. ISSN 0253-2964. http://koreascience.or.kr/journal/view.jsp?kj=JCGMCS&py=2005&vnc=v26n2&sp=340. 
  14. ↑ "The Effect of Trimebutine on the Overlap Syndrome Model of Guinea Pigs". Journal of Neurogastroenterology and Motility 24 (4): 669–675. October 2018. doi:10.5056/jnm18049. PMID 30114898. 
  15. ↑ 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 (Report). clinicaltrials.gov. 2013-11-08. https://clinicaltrials.gov/study/NCT01984931?intr=trimebutine. 
  16. ↑ 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 (Report). clinicaltrials.gov. 2023-01-30. https://clinicaltrials.gov/study/NCT02986685?intr=trimebutine. 
  17. ↑ Wallace JL, Cirino G, Santagada V, Caliendo G, "Salts of Trimebutine and N-Desmethyl Trimebutine", WO patent 2007/140611, published 13 December 2007
  18. ↑ "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 23: 100790. September 2020. doi:10.1016/j.bbrep.2020.100790. PMID 32760814. 
  19. ↑ "Nitric oxide as a regulator of inflammatory processes". Memórias do Instituto Oswaldo Cruz 100 (suppl 1): 5–9. March 2005. doi:10.1590/S0074-02762005000900002. PMID 15962091. 
  20. ↑ "Anti-inflammatory and cytoprotective properties of hydrogen sulfide". Hydrogen Sulfide in Redox Biology, Part B. Methods in Enzymology. 555. Academic Press. January 2015. pp. 169–193. doi:10.1016/bs.mie.2014.11.034. ISBN 978-0-12-801511-7. 
  21. ↑ "The protective impact of adapted trimebutine maleate-loaded nanostructured lipid carriers for alleviating the severity of acute colitis". Drug Delivery 29 (1): 906–924. December 2022. doi:10.1080/10717544.2022.2050847. PMID 35297699. 
  22. ↑ "Repositioning Trimebutine Maleate as a Cancer Treatment Targeting Ovarian Cancer Stem Cells". Cells 10 (4): 918. April 2021. doi:10.3390/cells10040918. PMID 33923707. 
  23. ↑ "Trimebutine Promotes Glioma Cell Apoptosis as a Potential Anti-tumor Agent". Frontiers in Pharmacology 9. 2018-06-21. doi:10.3389/fphar.2018.00664. PMID 29977208. 
  24. ↑ "Trimebutine prevents corneal inflammation in a rat alkali burn model". Scientific Reports 14 (1): 12111. May 2024. doi:10.1038/s41598-024-61112-4. PMID 38802470. Bibcode: 2024NatSR..1412111G. 
  25. ↑ "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 375 (1–2): 69–75. January 2007. doi:10.1016/j.cca.2006.06.006. PMID 16854404. 



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