Identification

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
Thumb
Synonyms
  • 2-Dimethylamino-2-phenylbutyl 3,4,5-trimethoxybenzoat
  • Trimébutine
  • Trimebutino
Product Ingredients
IngredientUNIICASInChI Key
Trimebutine maleate2A051GM4YM34140-59-5FSRLGULMGJGKGI-BTJKTKAUSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ModulonTablet200 mgOralAptalis Pharma Inc.1991-12-31Not applicableCanada
Modulon Inj 50mg/5mlLiquid10 mgIntramuscular; IntravenousAxcan Pharma1983-12-312000-01-07Canada
Modulon Tab 100mgTablet100 mgOralAxcan Pharma1983-12-312002-08-19Canada
TrimebutineTablet200 mgOralAa Pharma Inc2002-10-21Not applicableCanada
TrimebutineTablet100 mgOralAa Pharma Inc2002-10-21Not applicableCanada
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
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
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].

TargetActionsOrganism
AMu-type opioid receptor
agonist
Human
AVoltage dependent L type calcium channel
inhibitor
Human
ACalcium-activated potassium channel
inhibitor
Human
UVoltage-dependent T-type calcium channel
activator
Homo sapiens
AMuscarinic acetylcholine receptor M1
antagonist
Human
AMuscarinic acetylcholine receptor M2
antagonist
Human
AMuscarinic acetylcholine receptor M3
antagonist
Human
AMuscarinic acetylcholine receptor M4
antagonist
Human
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].

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
DrugInteraction
(R)-warfarinThe metabolism of Trimebutine can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Trimebutine.
1,10-PhenanthrolineThe therapeutic efficacy of Trimebutine can be decreased when used in combination with 1,10-Phenanthroline.
2,4-thiazolidinedioneThe risk or severity of hypoglycemia can be increased when Trimebutine is combined with 2,4-thiazolidinedione.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Trimebutine.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Trimebutine.
5-androstenedioneThe metabolism of Trimebutine can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Trimebutine can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Trimebutine.
9-aminocamptothecinThe metabolism of 9-aminocamptothecin can be decreased when combined with 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
AHFS Codes
  • 12:08.08 — Antimuscarinics Antispasmodics
  • 56:32.00 — Prokinetic Agents
MSDS
Download (33.4 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2, 3CompletedTreatmentIrritable Bowel Syndrome (IBS)1
3Unknown StatusPreventionNausea / Vomiting1
4CompletedTreatmentIrritable Bowel Syndrome (IBS)1
4RecruitingTreatmentRefractory Reflux Esophagitis1
Not AvailableSuspendedTreatmentHemorrhoids1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral200 mg
LiquidIntramuscular; Intravenous10 mg
TabletOral100 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)78-82Product monograph
water solubilityInsolubleProduct monograph
Predicted Properties
PropertyValueSource
Water Solubility0.019 mg/mLALOGPS
logP3.94ALOGPS
logP4.11ChemAxon
logS-4.3ALOGPS
pKa (Strongest Basic)8.48ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area57.23 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity108.94 m3·mol-1ChemAxon
Polarizability42.43 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0005-0923000000-c0a19149d59650fa4cd7
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0005-0913000000-86faf1281b06b2dec84c

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 / Aralkylamines
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 ether
show 18 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Voltage-gated calcium channel activity
Specific Function
Receptor for endogenous opioids such as beta-endorphin and endomorphin. Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone...
Gene Name
OPRM1
Uniprot ID
P35372
Uniprot Name
Mu-type opioid receptor
Molecular Weight
44778.855 Da
References
  1. Kaneto H, Takahashi M, Watanabe J: The opioid receptor selectivity for trimebutine in isolated tissues experiments and receptor binding studies. J Pharmacobiodyn. 1990 Jul;13(7):448-53. [PubMed:1963196]
Kind
Protein group
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated calcium channel activity
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...

Components:
References
  1. 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]
  2. 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]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated potassium channel activity
Specific Function
Potassium channel activated by both membrane depolarization or increase in cytosolic Ca(2+) that mediates export of K(+). It is also activated by the concentration of cytosolic Mg(2+). Its activati...
Gene Name
KCNMA1
Uniprot ID
Q12791
Uniprot Name
Calcium-activated potassium channel subunit alpha-1
Molecular Weight
137558.115 Da
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]
Kind
Protein group
Organism
Homo sapiens
Pharmacological action
Unknown
Actions
Activator
General Function
Scaffold protein binding
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...

Components:
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]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Phosphatidylinositol phospholipase c activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM1
Uniprot ID
P11229
Uniprot Name
Muscarinic acetylcholine receptor M1
Molecular Weight
51420.375 Da
References
  1. Eglen RM, Watson N: Selective muscarinic receptor agonists and antagonists. Pharmacol Toxicol. 1996 Feb;78(2):59-68. [PubMed:8822036]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
G-protein coupled acetylcholine receptor activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM2
Uniprot ID
P08172
Uniprot Name
Muscarinic acetylcholine receptor M2
Molecular Weight
51714.605 Da
References
  1. Eglen RM, Watson N: Selective muscarinic receptor agonists and antagonists. Pharmacol Toxicol. 1996 Feb;78(2):59-68. [PubMed:8822036]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Receptor activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM3
Uniprot ID
P20309
Uniprot Name
Muscarinic acetylcholine receptor M3
Molecular Weight
66127.445 Da
References
  1. Eglen RM, Watson N: Selective muscarinic receptor agonists and antagonists. Pharmacol Toxicol. 1996 Feb;78(2):59-68. [PubMed:8822036]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Guanyl-nucleotide exchange factor activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM4
Uniprot ID
P08173
Uniprot Name
Muscarinic acetylcholine receptor M4
Molecular Weight
53048.65 Da
References
  1. Eglen RM, Watson N: Selective muscarinic receptor agonists and antagonists. Pharmacol Toxicol. 1996 Feb;78(2):59-68. [PubMed:8822036]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Uesawa Y, Takeuchi T, Mohri K: Integrated analysis on the physicochemical properties of dihydropyridine calcium channel blockers in grapefruit juice interactions. Curr Pharm Biotechnol. 2012 Jul;13(9):1705-17. [PubMed:22039822]

Drug created on September 15, 2015 15:18 / Updated on December 12, 2018 07:20