Trimebutine

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Trimebutine
Trimebutine.svg
Clinical data
Trade names Debridat, Recutin, Polybutin, others
AHFS/Drugs.com International Drug Names
ATC code
Physiological data
Agonists opioid receptors
Antagonists mAChR, sodium channels
Pharmacokinetic data
Metabolites nortrimebutine, N-didesmethyltrimebutine, 2-dimethylamino-2-phenylbutan-1-ol, 2-methylamino-2-phenylbutan-1-ol, 2-amino-2-phenylbutan-1-ol
Elimination half-life 2.77 h (for oral dose 200 mg)
Excretion renal, fecal
Identifiers
  • 2-(Dimethylamino)-2-phenylbutyl 3,4,5-trimethoxybenzoate
CAS Number
PubChem CID
PubChemSID
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.049.354 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C22H29NO5
Molar mass 387.476 g·mol−1 X mark.svgN
3D model (JSmol)
Density 1.1±0.1 g/cm³ g/cm3
Boiling point 457.9 °C (856.2 °F) at 760 mmHg
  • CCC(COC(=O)C1=CC(=C(C(=C1)OC)OC)OC)(C2=CC=CC=C2)N(C)C
  • InChI=1S/C22H29NO5/c1-7-22(23(2)3,17-11-9-8-10-12-17)15-28-21(24)16-13-18(25-4)20(27-6)19(14-16)26-5/h8-14H,7,15H2,1-6H3 X mark.svgN
  • Key:LORDFXWUHHSAQU-UHFFFAOYSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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]

Contents

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 nad 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 thoughout 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 [12]

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.

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 Trimebutine synthesis.png
Trimebutine synthesis

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 adjuctive 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 anaglesic 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 suppresing Wnt, Notch and Hedgehod 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 dereased 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. ↑ Kaneto H, Takahashi M, Watanabe J (July 1990). "The opioid receptor selectivity for trimebutine in isolated tissues experiments and receptor binding studies". Journal of Pharmacobio-Dynamics. 13 (7): 448–453. doi: 10.1248/bpb1978.13.448 . hdl: 10069/38849 . PMID   1963196.
  2. ↑ "Libertrim SII". Medicamento SPLM. 17 February 2025.
  3. 1 2 "Debridat, 7,87 mg/g, granulat do sporządzania zawiesiny doustnej. Charakterystyka Produktu Leczniczego". Rejestr Produktów Leczniczych - Rejestry e-Zdrowia. 11 July 1996. Retrieved 18 February 2025.
  4. 1 2 Lee HT, Kim BJ (June 2011). "Trimebutine as a modulator of gastrointestinal motility". Archives of Pharmacal Research. 34 (6): 861–864. doi:10.1007/s12272-011-0600-7. PMID   21725804.
  5. ↑ Nagasaki M, Komori S, Ohashi H (September 1993). "Effect of trimebutine on voltage-activated calcium current in rabbit ileal smooth muscle cells". British Journal of Pharmacology. 110 (1): 399–403. doi:10.1111/j.1476-5381.1993.tb13823.x. PMC   2176005 . PMID   8220900.
  6. ↑ Tan W, Zhang H, Luo HS, Xia H (June 2011). "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. doi:10.1007/s12272-011-0615-0. PMID   21725819.
  7. 1 2 3 4 5 6 Trimebutine Maleate Tablets 100 mg and 200 mg. Lower gastrointestinal tract motility regulator, AA PHARMA Inc., July 1, 2010
  8. ↑ Hiyama T, Yoshihara M, Tanaka S, Haruma K, Chayama K (April 2009). "Effectiveness of prokinetic agents against diseases external to the gastrointestinal tract". Journal of Gastroenterology and Hepatology. 24 (4): 537–546. doi: 10.1111/j.1440-1746.2009.05780.x . PMID   19220673. S2CID   25767036.
  9. ↑ Pascaud X, Petoux F, Roman F, Vauche D, Junien JL. Mode d'action de la trimébutine. Implication des récepteurs opioïdes [Mode of action of trimebutine: involvement if opioid receptors]. Presse Med. 1989 Feb 15;18(6):298-302. French. PMID: 2537972.
  10. 1 2 3 4 Tribux Bio, 100 mg, tabletki. Charakterystyka Produktu Leczniczego, https://www.biofarm.pl/fileadmin/user_upload/Tribux_Bio_-_ChPL.pdf (access: 17.02.2025_
  11. ↑ Miura Y, Chishima S, Takeyama S: Studies of metabolic pathways of trimebutine by simultaneous administration of trimebutine and its deuterium-labeled metabolite. Drug Metab Dispos. 1989 Jul-Aug;17(4):455-62. (PubMed ID 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 EMA/409815/2020 Rev.21
  13. ↑ "A short Synthesis of Trimebutine, 2-Dimethylamino-2-phenylbutyl3,4,5-trimethylbenzoate". Bulletin of the Korean Chemical Society. 26 (2): 340–342. 2005-02-20. doi:10.5012/bkcs.2005.26.2.340. ISSN   0253-2964.
  14. ↑ Hussain Z, Jung DH, Lee YJ, Park H (October 2018). "The Effect of Trimebutine on the Overlap Syndrome Model of Guinea Pigs". Journal of Neurogastroenterology and Motility. 24 (4): 669–675. doi:10.5056/jnm18049. PMC   6175557 . PMID   30114898.
  15. ↑ Lhee SH (2013-11-08). 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.
  16. ↑ Shi Y (2023-01-30). 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.
  17. ↑ "SALTS OF TRIMEBUTINE AND N-DESMETHYL TRIMEBUTINE - Patent 2024323". data.epo.org. Retrieved 2025-02-17.
  18. ↑ Iwata M, Inoue T, Asai Y, Hori K, Fujiwara M, Matsuo S, et al. (September 2020). "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. doi:10.1016/j.bbrep.2020.100790. PMC   7390790 . PMID   32760814.
  19. ↑ Wallace JL (March 2005). "Nitric oxide as a regulator of inflammatory processes". Memórias do Instituto Oswaldo Cruz. 100 (suppl 1): 5–9. doi:10.1590/S0074-02762005000900002. PMID   15962091.
  20. ↑ Gemici B, Wallace JL (January 2015). "Anti-inflammatory and cytoprotective properties of hydrogen sulfide". In Cadenas E, Packer L (eds.). Hydrogen Sulfide in Redox Biology, Part B. Vol. 555. Academic Press. pp. 169–193. doi:10.1016/bs.mie.2014.11.034. ISBN   978-0-12-801511-7. PMID   25747480.{{cite book}}: |journal= ignored (help)
  21. ↑ Motawea A, Abd El Hady WE, Ahmed El-Emam G (December 2022). "The protective impact of adapted trimebutine maleate-loaded nanostructured lipid carriers for alleviating the severity of acute colitis". Drug Delivery. 29 (1): 906–924. doi:10.1080/10717544.2022.2050847. PMC   8933020 . PMID   35297699.
  22. ↑ Lee H, Kwon OB, Lee JE, Jeon YH, Lee DS, Min SH, et al. (April 2021). "Repositioning Trimebutine Maleate as a Cancer Treatment Targeting Ovarian Cancer Stem Cells". Cells. 10 (4): 918. doi: 10.3390/cells10040918 . PMC   8072797 . PMID   33923707.
  23. ↑ Fan YP, Liu P, Xue WK, Zhao WJ, Pan HC (2018-06-21). "Trimebutine Promotes Glioma Cell Apoptosis as a Potential Anti-tumor Agent". Frontiers in Pharmacology. 9: 664. doi: 10.3389/fphar.2018.00664 . PMC   6021541 . PMID   29977208.
  24. ↑ Goto H, Arima T, Takahashi A, Tobita Y, Nakano Y, Toda E, et al. (May 2024). "Trimebutine prevents corneal inflammation in a rat alkali burn model". Scientific Reports. 14 (1): 12111. Bibcode:2024NatSR..1412111G. doi:10.1038/s41598-024-61112-4. PMC   11130283 . PMID   38802470.
  25. ↑ Jhee OH, Lee YS, Shaw LM, Jeon YC, Lee MH, Lee SH, et al. (January 2007). "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. doi:10.1016/j.cca.2006.06.006. PMID   16854404.
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