Trimebutine

Identification

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Name

Trimebutine

Accession Number

DB09089

Type

Small Molecule

Groups

Approved

Description

Trimebutine is a spasmolytic agent that regulates intestinal and colonic motility and relieves abdominal pain with antimuscarinic and weak mu opioid agonist effects. It is marketed for the treatment of irritable bowel syndrome (IBS) and lower gastrointestinal tract motility disorders, with IBS being one of the most common multifactorial GI disorders ^[2]. It is used to restore normal bowel function and is commonly present in pharmaceutical mixtures as trimebutine maleate salt form. Trimebutine is not a FDA-approved drug, but it is available in Canada and several other international countries.

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Trimebutine (DB09089)

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Synonyms

• 2-Dimethylamino-2-phenylbutyl 3,4,5-trimethoxybenzoat
• Trimébutine
• Trimebutine
• Trimebutino

Product Ingredients

Ingredient	UNII	CAS	InChI Key
Trimebutine maleate	2A051GM4YM	34140-59-5	FSRLGULMGJGKGI-BTJKTKAUSA-N

Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Modulon	Tablet	200 mg	Oral	Aptalis Pharma Inc.	1991-12-31	Not applicable
Modulon Inj 50mg/5ml	Liquid	10 mg	Intramuscular; Intravenous	Axcan Pharma	1983-12-31	2000-01-07
Modulon Tab 100mg	Tablet	100 mg	Oral	Axcan Pharma	1983-12-31	2002-08-19
Trimebutine	Tablet	100 mg	Oral	Aa Pharma Inc	2002-10-21	Not applicable
Trimebutine	Tablet	200 mg	Oral	Aa Pharma Inc	2002-10-21	Not applicable

International/Other Brands

Altrip (Spedrog-Caillon, Argentina) / Anytin (Ahngook, South Korea) / Biorgan (Ivax, Argentina) / Bumetin (Galeno) / Butikinon (Towa Yakuhin) / Cerekinon (Mitsubishi Tanabe Pharma) / Cineprac (Liferpal, Mexico) / Colixane (Sanitas, Argentina) / Colonix (Grupo Farma, Ecuador) / Colperin (Gedeon Richter, Romania) / Coltrim (Novamed, Colombia) / Colypan (Grupo Farma) / Crobutin (Daewoo, South Korea) / Debretin (Polpharma, Poland) / Debricalm (Pfizer) / Debricol (Galpharma, Tunisia) / Debridat (Pfizer) / Digerent (Polifarma, Italy) / Diway (Poly Pharm, China) / Dolpic Forte (Laboratorios Pasteur, Chile) / Esun (Productos Farmaceuticos Medipharm, Chile) / Eumotil (Baliarda, Argentina) / Eumotrix (Lafrancol, Colombia) / Eutransil (Baliarda, Ecuador) / Fenatrop (Gador, Argentina) / Garapepsin (Farmellas Enterprises, Greece) / Gaspat (Indunidas, Ecuador) / Gast Reg (Amoun, Egypt) / Gismotal (Biofarma, Turkey) / Ircolon (Polfarmex, Poland) / Libertrim (Carnot Laboratorios, Mexico) / Mebucolon (Kyowa Yakuhin, Japan) / Mebutit (Sawai Seiyaku, Japan) / Miopropan (Bernabo, Argentina) / Neotina (Rossmore Pharma, Argentina) / Nepten (Nagase Medicals, Japan) / Newbutin SR (Korea United Pharm, Vietnam) / Ni Wei Fu (Anglikang Pharmaceutical, China) / Normopax (Eczane, Argentina) / Plidex (Roemmers, Argentina) / Polibutin (Desma, Spain) / Polybutine (Samil, South Korea) / Procinet NF (Eurofarma, Argentina) / Puridat Fort (Bilim, Turkey) / Rui Jian (Ante Bio-Pharmaceutical, China) / Sakion (Harasawa Seiyaku, Japan) / Shuang Di (Sanyu Pharmaceutical, China) / Spabutine (Hanmi, South Korea) / Supeslone (Koa Isei, Japan) / Tarabutine (Kukje, South Korea) / Tefmetin (Kobayashi Kako, Japan) / Tempolib (Medix, Mexico) / Tidomel (Laboratorios Euromed Chile, Chile) / Timotor (Square, Bangladesh) / Transacalm (Pharma Développement, France) / Trebutel (Laboratorios Andromaco, Chile) / Tribudat (Santa-Farma, Turkey; Sigma, Egypt) / Tributin (Incobra, Colombia) / Tributina (Lafedar, Argentina) / Tribux (Biofarm) / Trim (Laboratorio Saval, Chile) / Trimebutina (Anglopharma) / Trimedat (Life Pharma, Lebanon) / Trimedine (Opalia, Tunisia) / Trimotil (Incepta, Bangladesh) / Trimspa (Macleods, India) / VeM (Kyorin Rimedio, Japan) / Yuan Sheng Li Wei (Kaikai Yuansheng Medicine, China)

Categories

• Acids, Carbocyclic
• Agents causing hyperkalemia
• Agents producing tachycardia
• Alimentary Tract and Metabolism
• Antiarrhythmic agents
• Anticholinergic Agents
• Antimuscarinics Antispasmodics
• Autonomic Agents
• Benzene Derivatives
• Benzoates
• Bradycardia-Causing Agents
• Calcium Channel Blockers
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 CYP3A4 Substrates (strength unknown)
• Drugs for Functional Gastrointestinal Disorders
• Drugs that are Mainly Renally Excreted
• Ethers
• Gastrointestinal Agents
• Hydroxy Acids
• Hydroxybenzoate Ethers
• Hydroxybenzoates
• Muscarinic Antagonists
• Parasympatholytics
• Peripheral Nervous System Agents
• Phenols
• Phenyl Ethers
• Potential QTc-Prolonging Agents
• Prokinetic Agents
• QTc Prolonging Agents
• Synthetic Anticholinergics, Esters With Tertiary Amino Group

UNII

QZ1OJ92E5R

CAS number

39133-31-8

Weight

Average: 387.476
Monoisotopic: 387.204573038

Chemical Formula

C₂₂H₂₉NO₅

InChI Key

LORDFXWUHHSAQU-UHFFFAOYSA-N

InChI

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

IUPAC Name

2-(dimethylamino)-2-phenylbutyl 3,4,5-trimethoxybenzoate

SMILES

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

Pharmacology

Indication

Indicated for symptomatic treatment of irritable bowel syndrome (IBS) and treatment of postoperative paralytic ileus following abdominal surgery.

Associated Conditions

• Irritable Bowel Syndrome (IBS)
• Postoperative paralytic ileus

Pharmacodynamics

Trimebutine is a spasmolytic agent that acts directly on smooth muscle to modulate gastric motility. It shows a "dual function" that stimulates or inhibits spontaneous contractions depending on the concentration and prior contractile activity in the preparation. Targeting ion conductance that regulates GI motility, trimebutine inhibits the inward calcium currents and calcium-dependent potassium currents in a concentration-dependent manner ^[2]. At lower concentrations (1-10uM), trimebutine depolarizes the resting membrane potential without affecting the amplitude of contractions, which is thought to be mediated by inhibition of outward potassium currents. It is also shown to activate T-type Ca2+ channel and increase gastric emptying, intestinal and colonic contractility ^[1]. At higher concentrations (100-300uM), reduced amplitude of spontaneous contractions and action potentials is thought to be mediated by inhibition of L-type Ca2+ channels and inward calcium current ^[2]. Trimebutine mediates a local anesthetic action by acting as a weak agonist at mu opioid receptors.

Mechanism of action

At high concentrations, trimebutine is shown to inhibit the extracellular Ca2+ influx in the smooth muscle cells through voltage dependent L-type Ca2+ channels and further Ca2+ release from intracellular Ca2+ stores ^{[2, 4]}. Trimebutine is suggested to bind to the inactivated state of the calcium channel with high affinity. Reduced calcium influx attenuates membrane depolarization and decrease colon peristalsis. It also inhibits outward K+ currents in response to membrane depolarization of the GI smooth muscle cells at resting conditions through inhibition of delayed rectifier K+ channels and Ca2+ dependent K+ channels, which results in induced muscle contractions ^{[2, 6]}. Trimebutine binds to mu opioid receptors with more selectivity compared to delta or kappa opioid receptors but with lower affinity than their natural ligands. Its metabolites (N-monodesmethyl-trimebutine or nor-trimebutine), are also shown to bind to opoid receptors on brain membranes and myenteric synaptosomes ^[3].

Target	Actions	Organism
AMu-type opioid receptor	agonist	Humans
AVoltage-dependent L-type calcium channel	inhibitor	Humans
ACalcium-activated potassium channel	inhibitor	Humans
UVoltage-dependent T-type calcium channel	activator	Humans
AMuscarinic acetylcholine receptor M1	antagonist	Humans
AMuscarinic acetylcholine receptor M2	antagonist	Humans
AMuscarinic acetylcholine receptor M3	antagonist	Humans
AMuscarinic acetylcholine receptor M4	antagonist	Humans

Absorption

The free base form or salt form of trimebutine are rapidly absorbed after oral administration, with the peak plasma concentration reached after 1 hour of ingestion ^[3]. The time to reach peak plasma concentration following a single oral dose of 200mg trimebutine is 0.80 hours ^[8].

Volume of distribution

Trimebutine is most likely to be accumulated in the stomach and the intestinal walls in highest concentrations. The fetal transfer is reported to be low ^[3].

Protein binding

Protein binding is minimal with 5% in vivo and in vitro to serum albumin ^[8].

Metabolism

Trimebutine undergoes extensive hepatic first-pass metabolism. Nortrimebutine, or N-monodesmethyltrimebutine, is the main metabolite that retains pharmacological activity on the colon. This metabolite can undergo second N-demethylation to form N-didesmethyltrimebutine. Other main urinary metabolites (2-amino, 2-methylamino or 2-dimethylamino-2-phenylbutan-1-ol) can be formed via hydrolysis of the ester bond of desmethylated metabolites or initial hydrolysis of the ester bond of trimebutine followed by sequential N-demethylation ^[5]. Trimebutine is also prone to sulphate and/or glucuronic acid conjugation ^[8].

• Trimebutine
  Nortrimebutine
  • Nortrimebutine
    N-didesmethyltrimebutine
• Trimebutine
  2-dimethylamino-2-phenylbutan-1-ol
  • 2-dimethylamino-2-phenylbutan-1-ol
    2-methylamino-2-phenylbutan-1-ol
    • 2-methylamino-2-phenylbutan-1-ol
      2-amino-2-phenylbutan-1-ol

Route of elimination

Renal elimination is predominant while excretion into feces is also observed (5-12%). About 94% of an oral dose of trimebutine is eliminated by the kidneys in the form of various metabolites ^[3] and less than 2.4% of total ingested drug is recovered as unchanged parent drug in the urine ^[8].

Half life

The elimination half life is approximately 1 hour following a single oral dose of 2mg/kg ^[3], and 2.77 hours following a single oral dose 200 mg ^[8].

Clearance

Not Available

Toxicity

Common gastrointestinal adverse effects include dry mouth, foul taste, diarrhea, dyspepsia, epigastric pain, nausea and constipation. Some CNS effects include drowsiness, fatigue, dizziness, hot/cold sensations and headaches. In case of overdosage, gastric lavage is recommended. Oral LD50 in mouse and rats is >5000 mg/kg and 2500 mg/kg in rabbits, respectively. Trimebutine is not reported to display teratogenic, mutagenic or carcinogenic potential ^[8].

Affected organisms

Not Available

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

• All Drugs
• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental

Drug	Interaction
(R)-warfarin	The metabolism of Trimebutine can be decreased when combined with (R)-warfarin.
(S)-Warfarin	The metabolism of (S)-Warfarin can be decreased when combined with Trimebutine.
1,10-Phenanthroline	The therapeutic efficacy of Trimebutine can be decreased when used in combination with 1,10-Phenanthroline.
2,4-thiazolidinedione	The risk or severity of hypoglycemia can be increased when Trimebutine is combined with 2,4-thiazolidinedione.
2,5-Dimethoxy-4-ethylamphetamine	The risk or severity of Tachycardia can be increased when 2,5-Dimethoxy-4-ethylamphetamine is combined with Trimebutine.
2,5-Dimethoxy-4-ethylthioamphetamine	The risk or severity of Tachycardia can be increased when Trimebutine is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3,5-diiodothyropropionic acid	The metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Trimebutine.
4-Bromo-2,5-dimethoxyamphetamine	The risk or severity of Tachycardia can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Trimebutine.
4-hydroxycoumarin	The metabolism of 4-hydroxycoumarin can be decreased when combined with Trimebutine.
4-Methoxyamphetamine	4-Methoxyamphetamine may increase the central nervous system depressant (CNS depressant) activities of Trimebutine.

Food Interactions

Not Available

References

General References

1. Radulovic M, Anand P, Korsten MA, Gong B: Targeting Ion Channels: An Important Therapeutic Implication in Gastrointestinal Dysmotility in Patients With Spinal Cord Injury. J Neurogastroenterol Motil. 2015 Oct 1;21(4):494-502. doi: 10.5056/jnm15061. [PubMed:26424038]
2. Lee HT, Kim BJ: Trimebutine as a modulator of gastrointestinal motility. Arch Pharm Res. 2011 Jun;34(6):861-4. doi: 10.1007/s12272-011-0600-7. [PubMed:21725804]
3. Delvaux M, Wingate D: Trimebutine: mechanism of action, effects on gastrointestinal function and clinical results. J Int Med Res. 1997 Sep-Oct;25(5):225-46. [PubMed:9364286]
4. Nagasaki M, Komori S, Ohashi H: Effect of trimebutine on voltage-activated calcium current in rabbit ileal smooth muscle cells. Br J Pharmacol. 1993 Sep;110(1):399-403. [PubMed:8220900]
5. 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:2571489]
6. Tan W, Zhang H, Luo HS, Xia H: Effects of trimebutine maleate on colonic motility through Ca(2)+-activated K+ channels and L-type Ca(2)+ channels. Arch Pharm Res. 2011 Jun;34(6):979-85. doi: 10.1007/s12272-011-0615-0. Epub 2011 Jul 2. [PubMed:21725819]
7. Nagasaki M, Komori S, Tamaki H, Ohashi H: Effect of trimebutine on K+ current in rabbit ileal smooth muscle cells. Eur J Pharmacol. 1993 Apr 28;235(2-3):197-203. [PubMed:8389715]
8. AA Pharma Inc.: TRIMEBUTINE product monograph [Link]

External Links

PubChem Compound

5573

PubChem Substance

310265016

ChemSpider

5372

BindingDB

83417

ChEBI

94458

ChEMBL

CHEMBL190044

Wikipedia

Trimebutine

ATC Codes

A03AA05 — Trimebutine

• A03AA — Synthetic anticholinergics, esters with tertiary amino group
• A03A — DRUGS FOR FUNCTIONAL GASTROINTESTINAL DISORDERS
• A03 — DRUGS FOR FUNCTIONAL GASTROINTESTINAL DISORDERS
• A — ALIMENTARY TRACT AND METABOLISM

AHFS Codes

• 12:08.08 — Antimuscarinics Antispasmodics
• 56:32.00 — Prokinetic Agents

MSDS

Download (33.4 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
2, 3	Completed	Treatment	Irritable Bowel Syndrome (IBS)	1
3	Unknown Status	Prevention	Nausea / Vomiting	1
4	Completed	Treatment	Irritable Bowel Syndrome (IBS)	1
4	Recruiting	Treatment	Refractory Reflux Esophagitis	1
Not Available	Suspended	Treatment	Hemorrhoids	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage forms

Form	Route	Strength
Tablet	Oral	200 mg
Liquid	Intramuscular; Intravenous	10 mg
Tablet	Oral	100 mg

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	78-82	Product monograph
water solubility	Insoluble	Product monograph

Predicted Properties

Property	Value	Source
Water Solubility	0.019 mg/mL	ALOGPS
logP	3.94	ALOGPS
logP	4.11	ChemAxon
logS	-4.3	ALOGPS
pKa (Strongest Basic)	8.48	ChemAxon
Physiological Charge	1	ChemAxon
Hydrogen Acceptor Count	5	ChemAxon
Hydrogen Donor Count	0	ChemAxon
Polar Surface Area	57.23 Å2	ChemAxon
Rotatable Bond Count	10	ChemAxon
Refractivity	108.94 m3·mol-1	ChemAxon
Polarizability	42.43 Å3	ChemAxon
Number of Rings	2	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted ADMET features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	Not Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
MS/MS Spectrum - , positive	LC-MS/MS	splash10-0005-0923000000-c0a19149d59650fa4cd7
MS/MS Spectrum - , positive	LC-MS/MS	splash10-0005-0913000000-86faf1281b06b2dec84c

Taxonomy

Description

This compound belongs to the class of organic compounds known as gallic acid and derivatives. These are compounds containing a 3,4,5-trihydroxybenzoic acid moiety.

Kingdom

Organic compounds

Super Class

Benzenoids

Class

Benzene and substituted derivatives

Sub Class

Benzoic acids and derivatives

Direct Parent

Gallic acid and derivatives

Alternative Parents

M-methoxybenzoic acids and derivatives / P-methoxybenzoic acids and derivatives / Benzoic acid esters / Phenylpropanes / Methoxybenzenes / Benzoyl derivatives / Anisoles / Phenoxy compounds / Alkyl aryl ethers / AralkylaminesTrialkylamines / Carboxylic acid esters / Amino acids and derivatives / Monocarboxylic acids and derivatives / Organopnictogen compounds / Organic oxides / Hydrocarbon derivatives

show 7 more

Substituents

Gallic acid or derivatives / P-methoxybenzoic acid or derivatives / M-methoxybenzoic acid or derivatives / Benzoate ester / Phenylpropane / Phenoxy compound / Anisole / Benzoyl / Methoxybenzene / Phenol etherAlkyl aryl ether / Aralkylamine / Amino acid or derivatives / Tertiary aliphatic amine / Tertiary amine / Carboxylic acid ester / Carboxylic acid derivative / Ether / Monocarboxylic acid or derivatives / Organooxygen compound / Organic nitrogen compound / Hydrocarbon derivative / Organic oxide / Organopnictogen compound / Amine / Organonitrogen compound / Organic oxygen compound / Aromatic homomonocyclic compound

show 18 more

Molecular Framework

Aromatic homomonocyclic compounds

External Descriptors

Not Available

Drug created on September 15, 2015 15:18 / Updated on April 19, 2019 16:00