Identification
- Summary
Prucalopride is a 5-HT4 receptor agonist indicated to treat adults with chronic idiopathic constipation.
- Brand Names
- Motegrity, Resolor, Resotran
- Generic Name
- Prucalopride
- DrugBank Accession Number
- DB06480
- Background
Prucalopride is a dihydrobenzofurancarboxamide derivative from the benzofurane family that selectively stimulates 5-HT4 receptors and thus, it presents enterokinetic properties.2 The high selectivity of prucalopride allowed further development as it prevented the cardiac adverse reactions observed due to non-target effects of precedent therapies.5 Prucalopride was developed by Shire Development LLC and approved for use in Europe in 2009,1 in Canada on December 7, 2011 and by the FDA on December 17, 2018.7
- Type
- Small Molecule
- Groups
- Approved
- Structure
Structure for Prucalopride (DB06480)
- Weight
- Average: 367.87
Monoisotopic: 367.1662694 - Chemical Formula
- C18H26ClN3O3
- Synonyms
- Prucaloprida
- Prucalopride
- External IDs
- R-093877
- R093877
Pharmacology
- Indication
Prucalopride is indicated for the treatment of chronic idiopathic constipation (CIC) in adults.8
CIC is one of the most common chronic functional gastrointestinal disorders worldwide. The diagnosis of this agent is very hard and it can be confirmed if the patient experience at least two of the following:
-Straining during more than 25% of the bowel movements.
-Lumpy or hard stools in 25% of the bowel movements.
-Sensation of incomplete evacuation in more than 25% of all bowel movements.
-Sensation of anorectal blockage or obstruction in more than 25% of the bowel movements.
-Manual maneuvers required in more than 25% of the bowel movements.
-Fewer than 3 bowel movements per week.9
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Chronic idiopathic constipation •••••••••••• ••••• •••••• Treatment of Opioid-induced constipation ••• ••••• Treatment of Refractory chronic idiopathic constipation •••••••••••• ••••• ••••••• •••• •••••• - Contraindications & Blackbox Warnings
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In animal studies, prucalopride induced a dose-dependent stimulation of contractile activity in the proximal colon and inhibition of the contractility in the distal colon.4 As well it has been shown that prucalopride stimulates and amplifies giant migratory contraction which is the high-amplitude type of contraction that initiates the urge to defecate. Thus, prucalopride not only accelerates the colonic transit but also accelerates gastric emptying and small bowel transit.2
In supratherapeutic concentrations, prucalopride can be observed to interact with hERG potassium channels and L-type calcium channels.2
In clinical trials, prucalopride showed to significantly increase the spontaneous bowel movements with a standardized mean difference of about 0.5 after the use of 1 mg when compared with the placebo group.5 In this studies as well, it was observed a numerical improvement in mean colonic transit time and a significant increase in spontaneous complete bowel movement without marked changes in the anorectal function.5
In phase III clinical trials, 86% of the tested individuals opted to continue with the open-label study and based on Patients Assessments, 67% of the patients increase more than one point improvement in their satisfaction.5
In the final set of clinical trials for approval, there was a significant increase in the number of patients that reached over 3 complete spontaneous bowel movements per week when compared with the placebo.8
- Mechanism of action
Prucalopride acts as a selective stimulator of the 5-HT4 receptors while having no interaction with hERG channel or 5-HT1 receptors which reduces significantly the cardiovascular risk found in other similar drugs.1
5-HT4 receptors can be found throughout the gastrointestinal tract primarily in smooth muscle cells, enterochromaffin cells, and myenteric plexus. Its activation produces the release of acetylcholine which is the major excitatory neurotransmitter in the GI tract.2
Hence, prucalopride stimulates motility by interacting specifically with 5-HT4 receptors in the GI tract which causes a release of acetylcholine and further contraction of the muscle layer of the colon and relaxation of the circular muscle layer leading to the propulsion of luminal content.3
Target Actions Organism A5-hydroxytryptamine receptor 4 agonistHumans - Absorption
Prucalopride is well absorbed and it reaches maximum plasma concentration of 3.79ng/ml with a tmax of 2.77 hours after initial administration. It presents an AUC of 96.5 mn.h/ml.6 The bioavailability of prucalopride is of over 90% and this bioavailability does not get influenced by the ingestion of food.11
- Volume of distribution
The mean volume of distribution of prucalopride is registered to be 623 L.6
- Protein binding
The plasma protein binding of prucalopride is of 30%.11
- Metabolism
Prucalopride is not extensively metabolized in the body and does not interact with the enzymes of the family of the cytochrome P450 enzymes nor the P glycoprotein.2 The metabolism of prucalopride only represents 6% of the administered dose and the remaining 94% is found as the unchanged drug.6 From studies, it was reported the recovery of 8 metabolites being the major metabolite R107504 which is formed after the O-demethylation and oxidation of the resulting alcohol to a carboxylic acid.11
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- Route of elimination
After maximum plasma concentration, prucalopride concentration decline in a biphasic manner. Prucalopride is mainly excreted by the urine, representing 84% of the administered dose while only 13% of the dose is recovered in feces.6
- Half-life
The reported half-life of prucalopride is of around 18-20 hours.6
- Clearance
Prucalopride renal clearance is reported to be of 17 L/h which actually exceeds the glomerular filtration rate of the kidney.6
- Adverse Effects
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Prucalopride is well tolerated in doses reaching 10 times the recommended therapeutic dose and signs of overdose are thought to be stared by the presence of headaches, nausea and diarrhea.11 Carcinogenicity studies in mice indicated an increased incidence of mammary gland adenocarcinoma at a dose of 80 mg/kg/day. In rats, high doses were linked to increased incidence of benign adrenal pheochromocytoma, pituitary adenoma, pancreatic adenoma, hepatocellular adenoma and thyroid follicular tumors.12
For genotoxicity, prucalopride showed only one weak positive result in one of the five bacterial strain reverse mutation test at high concentrations.12 As well, there is no evidence of adverse effects on fertility, even in high doses.Label
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbacavir Abacavir may decrease the excretion rate of Prucalopride which could result in a higher serum level. Abametapir The serum concentration of Prucalopride can be increased when it is combined with Abametapir. Abrocitinib The serum concentration of Prucalopride can be increased when it is combined with Abrocitinib. Acalabrutinib The metabolism of Prucalopride can be decreased when combined with Acalabrutinib. Aceclofenac Aceclofenac may decrease the excretion rate of Prucalopride which could result in a higher serum level. - Food Interactions
- Take with or without food.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Prucalopride hydrochloride M8IYX9Z79V 179474-80-7 KKMOQGWTJRGLNN-UHFFFAOYSA-N Prucalopride succinate 4V2G75E1CK 179474-85-2 QZRSNVSQLGRAID-UHFFFAOYSA-N - International/Other Brands
- Resolor (Shire Pharmaceuticals Ireland Ltd)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Motegrity Tablet, film coated 2 mg/1 Oral Takeda Pharmaceuticals America, Inc. 2018-12-14 Not applicable US 
Motegrity Tablet, film coated 1 mg/1 Oral Takeda Pharmaceuticals America, Inc. 2018-12-14 Not applicable US Resolor Tablet, film coated 1 mg Oral Takeda Pharmaceuticals International Ag Ireland 2020-12-16 Not applicable EU 
Resolor Tablet, film coated 2 mg Oral Takeda Pharmaceuticals International Ag Ireland 2020-12-16 Not applicable EU Resolor Tablet, film coated 1 mg Oral Takeda Pharmaceuticals International Ag Ireland 2020-12-16 Not applicable EU - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Apo-prucalopride Tablet 2 mg Oral Apotex Corporation 2020-01-27 Not applicable Canada 
Apo-prucalopride Tablet 1 mg Oral Apotex Corporation 2020-01-27 Not applicable Canada Jamp Prucalopride Tablet 2 mg Oral Jamp Pharma Corporation 2021-02-26 Not applicable Canada Jamp Prucalopride Tablet 1 mg Oral Jamp Pharma Corporation 2021-02-26 Not applicable Canada PMS-prucalopride Tablet 1 mg Oral Pharmascience Inc Not applicable Not applicable Canada
Categories
- ATC Codes
- A06AX05 — Prucalopride
- Drug Categories
- Alimentary Tract and Metabolism
- Antidepressive Agents
- Central Nervous System Depressants
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates (strength unknown)
- Cytochrome P-450 Substrates
- Drugs for Constipation
- Drugs that are Mainly Renally Excreted
- Gastrointestinal Agents
- Heterocyclic Compounds, Fused-Ring
- Laxatives
- Miscellaneous GI Drugs
- Neurotransmitter Agents
- P-glycoprotein substrates
- Serotonin 4 Receptor Agonists
- Serotonin 5-HT4 Receptor Agonists
- Serotonin Agents
- Serotonin Receptor Agonists
- Serotonin-4 Receptor Agonist
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as aminobenzamides. These are organic compounds containing a benzamide moiety with an amine group attached to the benzene ring.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Benzoic acids and derivatives
- Direct Parent
- Aminobenzamides
- Alternative Parents
- Coumarans / Alkyl aryl ethers / Piperidines / Aryl chlorides / Trialkylamines / Secondary carboxylic acid amides / Amino acids and derivatives / Oxacyclic compounds / Dialkyl ethers / Azacyclic compounds show 5 more
- Substituents
- Alkyl aryl ether / Amine / Amino acid or derivatives / Aminobenzamide / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Carboxamide group / Carboxylic acid derivative show 19 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 0A09IUW5TP
- CAS number
- 179474-81-8
- InChI Key
- ZPMNHBXQOOVQJL-UHFFFAOYSA-N
- InChI
- InChI=1S/C18H26ClN3O3/c1-24-9-2-6-22-7-3-12(4-8-22)21-18(23)14-11-15(19)16(20)13-5-10-25-17(13)14/h11-12H,2-10,20H2,1H3,(H,21,23)
- IUPAC Name
- 4-amino-5-chloro-N-[1-(3-methoxypropyl)piperidin-4-yl]-2,3-dihydro-1-benzofuran-7-carboxamide
- SMILES
- COCCCN1CCC(CC1)NC(=O)C1=C2OCCC2=C(N)C(Cl)=C1
References
- General References
- Shin A, Camilleri M, Kolar G, Erwin P, West CP, Murad MH: Systematic review with meta-analysis: highly selective 5-HT4 agonists (prucalopride, velusetrag or naronapride) in chronic constipation. Aliment Pharmacol Ther. 2014 Feb;39(3):239-53. doi: 10.1111/apt.12571. Epub 2013 Dec 5. [Article]
- Omer A, Quigley EMM: An update on prucalopride in the treatment of chronic constipation. Therap Adv Gastroenterol. 2017 Nov;10(11):877-887. doi: 10.1177/1756283X17734809. Epub 2017 Oct 16. [Article]
- Briejer MR, Bosmans JP, Van Daele P, Jurzak M, Heylen L, Leysen JE, Prins NH, Schuurkes JA: The in vitro pharmacological profile of prucalopride, a novel enterokinetic compound. Eur J Pharmacol. 2001 Jun 29;423(1):71-83. [Article]
- Briejer MR, Prins NH, Schuurkes JA: Effects of the enterokinetic prucalopride (R093877) on colonic motility in fasted dogs. Neurogastroenterol Motil. 2001 Oct;13(5):465-72. [Article]
- Sajid MS, Hebbar M, Baig MK, Li A, Philipose Z: Use of Prucalopride for Chronic Constipation: A Systematic Review and Meta-analysis of Published Randomized, Controlled Trials. J Neurogastroenterol Motil. 2016 Jul 30;22(3):412-22. doi: 10.5056/jnm16004. [Article]
- Flach S, Scarfe G, Dragone J, Ding J, Seymour M, Pennick M, Pankratz T, Troy S, Getsy J: A Phase I Study to Investigate the Absorption, Pharmacokinetics, and Excretion of [(14)C]Prucalopride After a Single Oral Dose in Healthy Volunteers. Clin Ther. 2016 Sep;38(9):2106-15. doi: 10.1016/j.clinthera.2016.08.003. Epub 2016 Sep 7. [Article]
- FDA reports [Link]
- FDA approvals [Link]
- Canadian Society of Intestinal Research [Link]
- FDA Approved Drug Products: Motality (Prucalopride) Oral Tablets [Link]
- Resotrans (prucalopride) Australian label [File]
- Resotrans (prucalopride) Australian data sheet [File]
- External Links
- PubChem Compound
- 3052762
- PubChem Substance
- 310264873
- ChemSpider
- 2314539
- BindingDB
- 50122872
- 2107310
- ChEBI
- 135552
- ChEMBL
- CHEMBL117287
- ZINC
- ZINC000001891034
- Wikipedia
- Prucalopride
- FDA label
- Download (457 KB)
- MSDS
- Download (292 KB)
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Completed Other Chronic Constipation 1 4 Completed Treatment Chronic Constipation 1 4 Completed Treatment Constipation 2 4 Not Yet Recruiting Treatment Aspiration Pneumonia / Esophageal Motility Disorders / Gastric Motor Dysfunction / Gastroesophageal Reflux 1 4 Recruiting Other Satisfaction, Patient 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, film coated Oral 1 mg/1 Tablet, film coated Oral 2 mg/1 Tablet Oral Tablet, film coated Oral Tablet, film coated Oral 1 mg Tablet, film coated Oral 2 mg Tablet Oral 1 mg Tablet Oral 2 mg Tablet Oral 2.642 mg Tablet, coated Oral 1 mg Tablet, coated Oral 2 mg - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) >196 ºC 'MSDS' water solubility <1 mg/mL 'MSDS' logP 2.56 'MSDS' pKa 8.5 Resotrans data sheet (measure of piperidine moiety) - Predicted Properties
Property Value Source Water Solubility 0.129 mg/mL ALOGPS logP 2.09 ALOGPS logP 0.74 Chemaxon logS -3.5 ALOGPS pKa (Strongest Acidic) 14.64 Chemaxon pKa (Strongest Basic) 8.98 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 76.82 Å2 Chemaxon Rotatable Bond Count 6 Chemaxon Refractivity 100.67 m3·mol-1 Chemaxon Polarizability 39.08 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-014i-0009000000-e8cbc8c331de04394cef Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-014i-0009000000-474fdd9b863ee218d386 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-014i-0009000000-ba388989e08606fe6ee9 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-060r-2019000000-e3c8321e4d658de43d5d Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0fzd-1639000000-7ee92b5cf3c907b31331 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-001l-4095000000-f6816e8382673b761707 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 191.93472 predictedDeepCCS 1.0 (2019) [M+H]+ 194.29272 predictedDeepCCS 1.0 (2019) [M+Na]+ 200.38586 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Agonist
- General Function
- Serotonin receptor activity
- Specific Function
- This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor ...
- Gene Name
- HTR4
- Uniprot ID
- Q13639
- Uniprot Name
- 5-hydroxytryptamine receptor 4
- Molecular Weight
- 43760.975 Da
References
- Briejer MR, Bosmans JP, Van Daele P, Jurzak M, Heylen L, Leysen JE, Prins NH, Schuurkes JA: The in vitro pharmacological profile of prucalopride, a novel enterokinetic compound. Eur J Pharmacol. 2001 Jun 29;423(1):71-83. [Article]
- Grider JR, Foxx-Orenstein AE, Jin JG: 5-Hydroxytryptamine4 receptor agonists initiate the peristaltic reflex in human, rat, and guinea pig intestine. Gastroenterology. 1998 Aug;115(2):370-80. doi: 10.1016/s0016-5085(98)70203-3. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- 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
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Binder
- General Function
- Toxic substance binding
- Specific Function
- Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Serum albumin
- Molecular Weight
- 69365.94 Da
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- Multidrug resistance protein 1
- Molecular Weight
- 141477.255 Da
References
- Resolor (prucalopride) EMA label [Link]
Drug created at March 19, 2008 16:34 / Updated at February 20, 2024 23:55