Trimebutine is a drug withantimuscarinic and very weakmuopioidagonist effects.[1] It is used for the treatment ofirritable bowel syndrome and other gastrointestinal disorders. It is sometimes combined withsimethicone as a combination drug.[2] Trimebutine is formulated as a tablet or granules for oral suspension.[3]
Moreover, trimebutine andN-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 themigrating 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 insodium channels withIC50 equal 8.4 μM and inhibits glutamate release.[3]
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 serumalbumin binding is minimal.[7]Half-life (t1/2) of 200 mg timebutine maleate is equal to 2.77 h.[7]
Trimebutine exhibitsfirst-pass metabolism effect, which in turn generatesN-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 throughglucuronidation.[7]
According to European Medicines Agency, formulations of trimebutine might be contaminated withN-nitrosamines. However, it was assignedCPCA Category 5 with acceptable daily intake of 1500 ng/day.
Trimebutine can be synthesised from 1-phenylpropan-1-one (1). Firstly, it is converted to the corresponding oxirane throughtrimethylsulfoxonium idoide with sodium hydride inDMSO andTHF, yielding 2-ethyl-2-phenyl-oxirane (2). Next,2 undergoes ring-opening with dimethylaluminiumN,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) intriethylamine andTHF, which is catalysed by4-dimethylaminopyrridine (DMAP), yielding trimebutine.
Trimebutine maleate encapsulated by nanostructured lipid carriers was shown to induce protective effects on colon mucosa in acetic-acid colitis in rats.[21]
Heejinet al. showed that trimebutine is effective at stopping ovarian cancer cells from growingin 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 suppressingWnt,Notch andHedgehod pathways.[22]
Yi-pu Fanet. al found that trimebutine can inhibitglioma andglioblastoma cells from proliferating by promotingapoptosis and downregulation ofBcl-2, thereby upregulatingBax pro-apoptotic factor.[23]
Hitoshiet. al. showed that trimebutine can inhibit inflammation in corneal burns caused by alkali. This protective activity is thought to be mediated byhigh-mobility group box 1-receptor inhibitor, which causes decreased macrophage and neutrophil infiltration.[24]
^abLee 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.PMID21725804.
^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.PMID21725819.
^abcdefTrimebutine Maleate Tablets 100 mg and 200 mg. Lower gastrointestinal tract motility regulator, AA PHARMA Inc., July 1, 2010
^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.
^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)
^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
^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.ISBN978-0-12-801511-7.PMID25747480.{{cite book}}:|journal= ignored (help)
^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.PMID16854404.
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