Trimebutine is a drug with
antimuscarinic
A muscarinic acetylcholine receptor antagonist, also simply known as a muscarinic antagonist or as an antimuscarinic agent, is a type of anticholinergic drug that blocks the activity of the muscarinic acetylcholine receptors (mAChRs). The muscarin ...
and very weak
mu opioid
Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...
agonist
An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
effects. It is used for the treatment of
irritable bowel syndrome
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by a group of symptoms that commonly include abdominal pain, abdominal bloating, and changes in the consistency of bowel movements. These symptoms may ...
and other gastrointestinal disorders. It is sometimes combined with
simethicone
Simeticone (International Nonproprietary Name, INN), also known as simethicone (United States Adopted Name, USAN), is an anti-foaming agent used to reduce bloating, discomfort or pain caused by excessive gas.
Medical uses
Simeticone is used to ...
as a combination drug. Trimebutine is formulated as a tablet or granules for oral suspension.
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,
thereby decreasing calcium influx in smooth muscle in the gut. This mechanism explains its ability to slow
peristalsis
Peristalsis ( , ) is a type of intestinal motility, characterized by symmetry in biology#Radial symmetry, radially symmetrical contraction and relaxation of muscles that propagate in a wave down a tube, in an wikt:anterograde, anterograde dir ...
, which in turn helps with
diarrhoea
Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...
management in IBS patients.
Antispasmodic
An antispasmodic (synonym: spasmolytic) is a pharmaceutical drug or other agent that suppresses muscle spasms.
Smooth muscle spasm
One type of antispasmodics is used for smooth muscle relaxation, especially in tubular organs of the gastrointestina ...
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
mAChRs
Muscarinic acetylcholine receptors (mAChRs) are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-recepto ...
, which is believed to potentiate its antispasmodic effects, as do many other
drugs in this class.
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 Migrating motor complex, also known as migrating myoelectric complex, migratory motor complex, migratory myoelectric complex and MMC, is a cyclic, recurring motility pattern that occurs in the stomach and small bowel during fasting; it is interrupte ...
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.
''In vitro'', trimebutine also exhibits antagonistic effects in
sodium channels
Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels.
Classification
They are classified into 2 types:
Function
In e ...
with
IC50 equal 8.4 μM and inhibits glutamate release.
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
[Tribux Bio, 100 mg, tabletki. Charakterystyka Produktu Leczniczego, https://www.biofarm.pl/fileadmin/user_upload/Tribux_Bio_-_ChPL.pdf (access: 17.02.2025_] and 0.88 h for 200 mg dose.
[Trimebutine Maleate Tablets 100 mg and 200 mg. Lower gastrointestinal tract motility regulator, AA PHARMA Inc., July 1, 2010] The level of serum
albumin
Albumin is a family of globular proteins, the most common of which are the serum albumins. All of the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Alb ...
binding is minimal.
Half-life (t1/2) of 200 mg timebutine maleate is equal to 2.77 h.
Metabolism and excretion
Trimebutine exhibits
first-pass metabolism
The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism at a specific location in the body which leads to a reduction in the concentration of the active drug before it reaches the ...
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
Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gly ...
.
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.
Interactions
Trimebutine can increase the length of anaesthesia induced with d-tubocurarine.
Other interactions include:
* potentiation of anticholinergic effects caused by
zotepine
Zotepine is an atypical antipsychotic drug indicated for acute and chronic schizophrenia. It has been used in Germany since 1990 (although it has been discontinued in Germany) and Japan since 1982.
Zotepine is not approved for use in the United ...
* decreasing efficacy of
cisapride
Cisapride is a gastroprokinetic agent, a drug that increases motility in the upper gastrointestinal tract. It acts directly as a serotonin 5-HT4 receptor agonist and indirectly as a parasympathomimetic. Stimulation of the serotonin receptors incr ...
*
procainamide
Procainamide (PCA) is a medication of the antiarrhythmic class used for the treatment of cardiac arrhythmias. It is a sodium channel blocker of cardiomyocytes; thus it is classified by the Vaughan Williams classification system as class Ia. ...
(potentiation of
vagus nerve
The vagus nerve, also known as the tenth cranial nerve (CN X), plays a crucial role in the autonomic nervous system, which is responsible for regulating involuntary functions within the human body. This nerve carries both sensory and motor fibe ...
activity inhibition, thereby causing a positive
chronotropic effect and, in turn,
tachycardia
Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ...
)
*
calcium channel blockers
Calcium channel blockers (CCB), calcium channel antagonists or calcium antagonists are a group of medications that disrupt the movement of calcium () through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e., a ...
Adverse effects
Trimebutine may cause following side-effects:
* psychiatric disturbances:
anxiety
Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...
* CNS reactions:
somnolence
Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling aslee ...
,
malaise
In medicine, malaise is a feeling of general discomfort, uneasiness or lack of wellbeing and often the first sign of an infection or other disease. It is considered a vague termdescribing the state of simply not feeling well. The word has exist ...
,
vertigo
Vertigo is a condition in which a person has the sensation that they are moving, or that objects around them are moving, when they are not. Often it feels like a spinning or swaying movement. It may be associated with nausea, vomiting, perspira ...
,
paresthesia
Paresthesia is a sensation of the skin that may feel like numbness (''hypoesthesia''), tingling, pricking, chilling, or burning. It can be temporary or Chronic condition, chronic and has many possible underlying causes. Paresthesia is usually p ...
,
headache
A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...
,
apathy
Apathy, also referred to as indifference, is a lack of feeling, emotion, interest, or concern about something. It is a state of indifference, or the suppression of emotions such as concern, excitement, motivation, or passion. An apathetic i ...
* ear problems:
hearing loss
Hearing loss is a partial or total inability to hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to acquire spo ...
* heart problems: tachycardia
* GI reactions:
xerostomia
Xerostomia, also known as dry mouth, is a subjective complaint of dryness in the mouth, which may be associated with a change in the composition of saliva, reduced salivary flow, or have no identifiable cause.
This symptom is very common and is o ...
, taste disorders,
diarrhoea
Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...
,
dyspepsia
Indigestion, also known as dyspepsia or upset stomach, is a condition of impaired digestion. Symptoms may include upper abdominal fullness, heartburn, nausea, belching, or upper abdominal pain. People may also experience feeling full earlier ...
, upper quadrant pain, lip paresthesia,
nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat.
Over 30 d ...
,
vomiting
Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose.
Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...
,
constipation
Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...
, excessive thirst
* hepatic and bile ducts reactions:
hepatic insufficiency,
hepatitis
Hepatitis is inflammation of the liver parenchyma, liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), Anorexia (symptom), poor appetite ...
, increased
liver enzymes
Liver function tests (LFTs or LFs), also referred to as a hepatic panel or liver panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial t ...
* skin and soft tissue reactions: rash,
pruritus
An itch (also known as pruritus) is a sensation that causes a strong desire or reflex to scratch. Itches have resisted many attempts to be classified as any one type of sensory experience. Itches have many similarities to pain, and while both ...
,
urticaria
Hives, also known as urticaria, is a kind of skin rash with red or flesh-colored, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and typically ...
, flushing,
blistering
A blister is a small pocket of fluid in the upper layer of the skin caused by heat, electricity, chemicals, light, radiation, or friction
Blister(s) or Blistering may also refer to:
* Blood blister
* Bleb (medicine)
* Anti-torpedo bulge, also know ...
, lumps, exudation,
erythema multiforme
Erythema multiforme (EM) is an immune-mediated inflammatory skin condition associated with several viral infections, that appears with red patches evolving into target lesions, typically on both hands. It is typically associated with infection ...
* renal reactions:
urinary retention
Urinary retention is an inability to completely empty the bladder. Onset can be sudden or gradual. When of sudden onset, symptoms include an inability to urinate and lower abdominal pain. When of gradual onset, symptoms may include urinary incont ...
* reproductive system reactions:
dysmenorrhoea
Dysmenorrhea, also known as period pain, painful periods or menstrual cramps, is pain during menstruation. Its usual onset occurs around the time that menstruation begins. Symptoms typically last less than three days. The pain is usually in the ...
,
mastitis
Mastitis is inflammation of the breast or udder, usually associated with breastfeeding. Symptoms typically include local pain and redness. There is often an associated fever and general soreness. Onset is typically fairly rapid and usually occ ...
,
gynceomastia in males, breast pain
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
Dimethyl sulfoxide (DMSO) is an organosulfur compound with the formula . This colorless liquid is the sulfoxide most widely used commercially. It is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is ...
and
THF
Tetrahydrofuran (THF), or oxolane, is an organic compound with the formula (CH2)4O. The compound is classified as heterocyclic compound, specifically a cyclic ether. It is a colorless, water-miscible organic liquid with low viscosity. It is ma ...
, 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
Triethylamine is the chemical compound with the formula N(CH2CH3)3, commonly abbreviated Et3N. Like triethanolamine and the tetraethylammonium ion, it is often abbreviated TEA. It is a colourless volatile liquid with a strong fishy odor remini ...
and
THF
Tetrahydrofuran (THF), or oxolane, is an organic compound with the formula (CH2)4O. The compound is classified as heterocyclic compound, specifically a cyclic ether. It is a colorless, water-miscible organic liquid with low viscosity. It is ma ...
, which is catalysed by
4-dimethylaminopyrridine (DMAP), yielding trimebutine.
Research
Trimebutine is investigated for the treatment of
functional dyspepsia
Functional dyspepsia (FD) is a common gastrointestinal disorder defined by symptoms arising from the gastroduodenal region in the absence of an underlying organic disease that could easily explain the symptoms. Characteristic symptoms include ep ...
-IBS
overlap syndrome,
post-operative nausea and vomiting
Postoperative nausea and vomiting (PONV) is the common complication of nausea, vomiting, or retching experienced by a person within the first 24 hours following a surgical procedure. Untreated, PONV affects about 30% of people undergoing general an ...
. A clinical trial evaluating trimebutine as an adjunctive treatment to
rabeprazole
Rabeprazole, sold under the brand name Aciphex, among others, is a medication that decreases stomach acid. It is used to treat peptic ulcer disease, gastroesophageal reflux disease, and excess stomach acid production such as in Zollinger–Ell ...
-resistant
reflux oesophageitis was withdrawn due to lack of funds.
Novel salts of trimebutine
Wallace ''et al.'' synthesised several new salts with improved analgesic properties in patients with irritable bowel syndrome. These include:
* trimebutine nitroarginate and derivatives – arginine
nitro-derivative acts as a
nitric oxide
Nitric oxide (nitrogen oxide, nitrogen monooxide, or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes den ...
donor, which exerts anti-inflammatory effect (similarly to
naproxcinod
Naproxcinod (nitronaproxen) is a nonsteroidal anti-inflammatory drug (NSAID) developed by the French pharmaceutical company NicOx. It is a derivative of naproxen with a nitroxybutyl ester to allow it to also act as a nitric oxide (NO) donor. Th ...
)
* trimebutine thiocarbamoylbenzoate –
thioamide
A thioamide (rarely, thionamide, but also known as thiourylenes) is a functional group with the general structure , where are any groups (typically organyl groups or hydrogen). Analogous to amides, thioamides exhibit greater multiple bond charact ...
group acts as a
hydrogen sulfide
Hydrogen sulfide is a chemical compound with the formula . It is a colorless chalcogen-hydride gas, and is toxic, corrosive, and flammable. Trace amounts in ambient atmosphere have a characteristic foul odor of rotten eggs. Swedish chemist ...
donor, also acting as an anti-inflammatory and analgesic agent
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.
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
Hedgehod pathways.
Yi-pu Fan ''et. al'' found that trimebutine can inhibit
glioma
A glioma is a type of primary tumor that starts in the glial cells of the brain or spinal cord. They are malignant but some are extremely slow to develop. Gliomas comprise about 30% of all brain and central nervous system tumors and 80% of ...
and
glioblastoma
Glioblastoma, previously known as glioblastoma multiforme (GBM), is the most aggressive and most common type of cancer that originates in the brain, and has a very poor prognosis for survival. Initial signs and symptoms of glioblastoma are nons ...
cells from proliferating by promoting
apoptosis
Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
and downregulation of
Bcl-2
Bcl-2, encoded in humans by the ''BCL2'' gene, is the founding member of the Bcl-2 family of regulator proteins. BCL2 blocks programmed cell death (apoptosis) while other BCL2 family members can either inhibit or induce it. It was the first a ...
, thereby upregulating
Bax pro-apoptotic factor.
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.
Brand names
The
maleic acid
Maleic acid or ''cis''-butenedioic acid is an organic compound that is a dicarboxylic acid, a molecule with two carboxyl groups. Its chemical formula is HO2CCH=CHCO2H. Maleic acid is the ''cis'' Cis–trans isomerism, isomer of butenedioic acid, ...
salt of trimebutine is marketed under the
trademark
A trademark (also written trade mark or trade-mark) is a form of intellectual property that consists of a word, phrase, symbol, design, or a combination that identifies a Good (economics and accounting), product or Service (economics), service f ...
s 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.
See also
*
Asimadoline
*
Fedotozine
Fedotozine (INN; JO 1196 for the (-) tartrate salt) is an opioid drug which acts as a peripherally specific selective κ1-opioid receptor agonist with preference for the κ1A subtype. It was under investigation for the treatment of gastrointe ...
References
{{Opioid receptor modulators
Benzoate esters
Dimethylamino compounds
M1 receptor antagonists
M2 receptor antagonists
M3 receptor antagonists
M4 receptor antagonists
M5 receptor antagonists
Mu-opioid receptor agonists
Phenol ethers