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Identification
- Summary
Naldemedine is an opioid antagonist used to to treat opioid-induced constipation.
- Brand Names
- Symproic
- Generic Name
- Naldemedine
- DrugBank Accession Number
- DB11691
- Background
Naldemedine is an opioid receptor antagonist Label. It is a modified form of Naltrexone to which a side chain has been added to increase molecular weight and polar surface area resulting in restricted transport across the blood brain barrier. Naldemedine was approved in 2017 in both the US and Japan for the treatment of Opioid-induced Constipation.
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Naldemedine (DB11691)
- Weight
- Average: 570.646
Monoisotopic: 570.247834831 - Chemical Formula
- C32H34N4O6
- Synonyms
- Naldemedine
- External IDs
- S-297995
Pharmacology
- Indication
For the treatment of opioid-induced constipation Label.
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Opioid-induced constipation •••••••••••• ••••• - Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- Pharmacodynamics
Naldemedine is an opioid receptor antagonist with restricted movement across the blood brain barrier Label. This allows it to antagonize the periperal effects of opioid drugs such as constipation without interfering with the effects on the central nervous system.
- Mechanism of action
Naldemedine binds to and antagonizes mu-, delta-, and kappa-opioid receptors Label. The binding of opioid agonists to peripheral mu-opioid receptors slows the transit of feces through the intestine resulting in constipation. By antagonizing mu-opioid receptors, naldemedine inhibits this effect.
Target Actions Organism AMu-type opioid receptor antagonistHumans ADelta-type opioid receptor antagonistHumans AKappa-type opioid receptor antagonistHumans - Absorption
Tmax is 0.75 h Label. Administration with a high-fat meal reduces Cmax by 35% and increases Tmax to 2.5 h.
- Volume of distribution
The apparent volume of disribution during the terminal phase is 155 L Label
- Protein binding
Naldemedine is 93-94% bound to human plasma proteins Label.
- Metabolism
Naldemedine is mainly metabolized to nor-naldemedine by CYP3A Label. Some metabolism to naldemedine-3-glucuronide occurs via UGT1A3. Both metabolites are acitive but less potent than naldemedine. The relative exposures of these metabolites are 9-13% and <3% for nor-naldemedine and naldemedine-3-glucuronide respectively. Naldemedine is also cleaved in the intestine to form benzamidine and naldemedine carboxylic acid.
- Route of elimination
57% of naldemedine is excreted in the urine with 16-18% as the parent compound and 35% is excreted in the feces Label.
- Half-life
The terminal elimination half life is 11 h Label.
- Clearance
Not Available
- Adverse Effects
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The most common adverse effects of naldemedine are abdominal pain (11%), diarrhea (7%), nausea (6%), vomiting (3%), and gastroenteritis (3%) Label.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- 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 Naldemedine which could result in a higher serum level. Aceclofenac Aceclofenac may decrease the excretion rate of Naldemedine which could result in a higher serum level. Acemetacin Acemetacin may decrease the excretion rate of Naldemedine which could result in a higher serum level. Acetaminophen Acetaminophen may decrease the excretion rate of Naldemedine which could result in a higher serum level. Acetazolamide Acetazolamide may increase the excretion rate of Naldemedine which could result in a lower serum level and potentially a reduction in efficacy. - Food Interactions
- Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of naldemedine.
- 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 Naldemedine tosylate V1N8F1RVVO 1345728-04-2 WCYDLROFMZJJLE-RTMHEQJQSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Rizmoic Tablet, film coated 200 mcg Oral Shionogi 2020-12-16 Not applicable EU 
Rizmoic Tablet, film coated 200 mcg Oral Shionogi 2020-12-16 Not applicable EU Rizmoic Tablet, film coated 200 mcg Oral Shionogi 2020-12-21 Not applicable EU Rizmoic Tablet, film coated 200 mcg Oral Shionogi 2020-12-16 Not applicable EU Rizmoic Tablet, film coated 200 mcg Oral Shionogi 2020-12-16 Not applicable EU
Categories
- ATC Codes
- A06AH05 — Naldemedine
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as morphinans. These are polycyclic compounds with a four-ring skeleton with three condensed six-member rings forming a partially hydrogenated phenanthrene moiety, one of which is aromatic while the two others are alicyclic.
- Kingdom
- Organic compounds
- Super Class
- Alkaloids and derivatives
- Class
- Morphinans
- Sub Class
- Not Available
- Direct Parent
- Morphinans
- Alternative Parents
- Phenanthrenes and derivatives / Phenyloxadiazoles / Tetralins / Coumarans / 1-hydroxy-2-unsubstituted benzenoids / Alkyl aryl ethers / Aralkylamines / Piperidines / Benzene and substituted derivatives / Vinylogous acids show 13 more
- Substituents
- 1,2,4-oxadiazole / 1,2-aminoalcohol / 1-hydroxy-2-unsubstituted benzenoid / Alcohol / Alkyl aryl ether / Amine / Amino acid or derivatives / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle show 31 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 03KSI6WLXH
- CAS number
- 916072-89-4
- InChI Key
- AXQACEQYCPKDMV-RZAWKFBISA-N
- InChI
- InChI=1S/C32H34N4O6/c1-30(2,29-33-27(35-42-29)18-6-4-3-5-7-18)34-28(39)20-15-32(40)22-14-19-10-11-21(37)25-23(19)31(32,26(41-25)24(20)38)12-13-36(22)16-17-8-9-17/h3-7,10-11,17,22,26,37-38,40H,8-9,12-16H2,1-2H3,(H,34,39)/t22-,26+,31+,32-/m1/s1
- IUPAC Name
- (1S,5R,13R,17S)-4-(cyclopropylmethyl)-10,14,17-trihydroxy-N-[2-(3-phenyl-1,2,4-oxadiazol-5-yl)propan-2-yl]-12-oxa-4-azapentacyclo[9.6.1.0^{1,13}.0^{5,17}.0^{7,18}]octadeca-7,9,11(18),14-tetraene-15-carboxamide
- SMILES
- [H][C@@]12OC3=C4C(C[C@@]5([H])N(CC6CC6)CC[C@@]14[C@@]5(O)CC(C(=O)NC(C)(C)C1=NC(=NO1)C1=CC=CC=C1)=C2O)=CC=C3O
References
- General References
- FDA Approved Drug Products: Symproic (naldemidine tosylate) tablets for oral use [Link]
- External Links
- PubChem Compound
- 54732242
- PubChem Substance
- 347828056
- ChemSpider
- 28530803
- BindingDB
- 50503604
- 1876597
- ChEMBL
- CHEMBL2105755
- Wikipedia
- Naldemedine
- FDA label
- Download (209 KB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Recruiting Not Available Opioid Induced Constipation (OIC) 1 somestatus stop reason just information to hide 3 Completed Treatment Opioid Induced Constipation (OIC) 3 somestatus stop reason just information to hide 2 Completed Treatment Opioid Induced Bowel Dysfunction 1 somestatus stop reason just information to hide 2 Completed Treatment Opioid Induced Constipation (OIC) 1 somestatus stop reason just information to hide 2 Recruiting Treatment Constipation / Opioid Induced Bowel Dysfunction 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, film coated Oral 200 MCG Tablet Oral .2 mg/1 Tablet Oral 0.2 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US9108975 No 2015-08-18 2031-11-11 US 
USRE46365 No 2017-04-11 2028-01-11 US USRE46375 No 2017-04-25 2026-10-05 US US10952968 No 2021-03-23 2033-05-13 US
Properties
- State
- Not Available
- Experimental Properties
Property Value Source water solubility Slightly soluble FDA Label - Predicted Properties
Property Value Source Water Solubility 0.227 mg/mL ALOGPS logP 3.14 ALOGPS logP 2.43 Chemaxon logS -3.4 ALOGPS pKa (Strongest Acidic) 9.86 Chemaxon pKa (Strongest Basic) 9.05 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 8 Chemaxon Hydrogen Donor Count 4 Chemaxon Polar Surface Area 141.18 Å2 Chemaxon Rotatable Bond Count 6 Chemaxon Refractivity 165.78 m3·mol-1 Chemaxon Polarizability 61.34 Å3 Chemaxon Number of Rings 8 Chemaxon Bioavailability 1 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 230.58621 predictedDeepCCS 1.0 (2019) [M+H]+ 232.57835 predictedDeepCCS 1.0 (2019) [M+Na]+ 238.31877 predictedDeepCCS 1.0 (2019)
Targets
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Receptor for endogenous opioids such as beta-endorphin and endomorphin (PubMed:10529478, PubMed:12589820, PubMed:7891175, PubMed:7905839, PubMed:7957926, PubMed:9689128). Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone (PubMed:10529478, PubMed:10836142, PubMed:12589820, PubMed:19300905, PubMed:7891175, PubMed:7905839, PubMed:7957926, PubMed:9689128). Also activated by enkephalin peptides, such as Met-enkephalin or Met-enkephalin-Arg-Phe, with higher affinity for Met-enkephalin-Arg-Phe (By similarity). Agonist binding to the receptor induces coupling to an inactive GDP-bound heterotrimeric G-protein complex and subsequent exchange of GDP for GTP in the G-protein alpha subunit leading to dissociation of the G-protein complex with the free GTP-bound G-protein alpha and the G-protein beta-gamma dimer activating downstream cellular effectors (PubMed:7905839). The agonist- and cell type-specific activity is predominantly coupled to pertussis toxin-sensitive G(i) and G(o) G alpha proteins, GNAI1, GNAI2, GNAI3 and GNAO1 isoforms Alpha-1 and Alpha-2, and to a lesser extent to pertussis toxin-insensitive G alpha proteins GNAZ and GNA15 (PubMed:12068084). They mediate an array of downstream cellular responses, including inhibition of adenylate cyclase activity and both N-type and L-type calcium channels, activation of inward rectifying potassium channels, mitogen-activated protein kinase (MAPK), phospholipase C (PLC), phosphoinositide/protein kinase (PKC), phosphoinositide 3-kinase (PI3K) and regulation of NF-kappa-B (By similarity). Also couples to adenylate cyclase stimulatory G alpha proteins (By similarity). The selective temporal coupling to G-proteins and subsequent signaling can be regulated by RGSZ proteins, such as RGS9, RGS17 and RGS4 (By similarity). Phosphorylation by members of the GPRK subfamily of Ser/Thr protein kinases and association with beta-arrestins is involved in short-term receptor desensitization (By similarity). Beta-arrestins associate with the GPRK-phosphorylated receptor and uncouple it from the G-protein thus terminating signal transduction (By similarity). The phosphorylated receptor is internalized through endocytosis via clathrin-coated pits which involves beta-arrestins (By similarity). The activation of the ERK pathway occurs either in a G-protein-dependent or a beta-arrestin-dependent manner and is regulated by agonist-specific receptor phosphorylation (By similarity). Acts as a class A G-protein coupled receptor (GPCR) which dissociates from beta-arrestin at or near the plasma membrane and undergoes rapid recycling (By similarity). Receptor down-regulation pathways are varying with the agonist and occur dependent or independent of G-protein coupling (By similarity). Endogenous ligands induce rapid desensitization, endocytosis and recycling (By similarity). Heterooligomerization with other GPCRs can modulate agonist binding, signaling and trafficking properties (By similarity)
- Specific Function
- beta-endorphin receptor activity
- Gene Name
- OPRM1
- Uniprot ID
- P35372
- Uniprot Name
- Mu-type opioid receptor
- Molecular Weight
- 44778.855 Da
References
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- G-protein coupled receptor that functions as a receptor for endogenous enkephalins and for a subset of other opioids. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling leads to the inhibition of adenylate cyclase activity. Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Plays a role in the perception of pain and in opiate-mediated analgesia. Plays a role in developing analgesic tolerance to morphine
- Specific Function
- G protein-coupled enkephalin receptor activity
- Gene Name
- OPRD1
- Uniprot ID
- P41143
- Uniprot Name
- Delta-type opioid receptor
- Molecular Weight
- 40368.235 Da
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- G-protein coupled opioid receptor that functions as a receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. Also functions as a receptor for various synthetic opioids and for the psychoactive diterpene salvinorin A. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling leads to the inhibition of adenylate cyclase activity. Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Plays a role in the perception of pain. Plays a role in mediating reduced physical activity upon treatment with synthetic opioids. Plays a role in the regulation of salivation in response to synthetic opioids. May play a role in arousal and regulation of autonomic and neuroendocrine functions
- Specific Function
- dynorphin receptor activity
- Gene Name
- OPRK1
- Uniprot ID
- P41145
- Uniprot Name
- Kappa-type opioid receptor
- Molecular Weight
- 42644.665 Da
Enzymes
- Kind
- Protein group
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
- Specific Function
- 1,8-cineole 2-exo-monooxygenase activity
Components:
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:15472229, PubMed:18674515, PubMed:18719240, PubMed:23288867, PubMed:23756265, PubMed:24641623). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:23756265). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol and estrone (PubMed:15472229, PubMed:18719240, PubMed:23288867). Contributes to bile acid (BA) detoxification by catalyzing the glucuronidation of BA substrates, which are natural detergents for dietary lipids absorption (PubMed:23756265). Involved in the glucuronidation of calcidiol, which is the major circulating form of vitamin D3, essential for the regulation of calcium and phosphate homeostasis (PubMed:24641623). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonists losartan, candesartan and zolarsartan, which can inhibit the effect of angiotensin II (PubMed:18674515)
- Specific Function
- enzyme binding
- Gene Name
- UGT1A3
- Uniprot ID
- P35503
- Uniprot Name
- UDP-glucuronosyltransferase 1A3
- Molecular Weight
- 60337.835 Da
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Energy-dependent efflux transporter responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:12960149, PubMed:15205344, PubMed:15899824, PubMed:22306008). Specifically present in limbal stem cells, where it plays a key role in corneal development and repair (By similarity)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCB5
- Uniprot ID
- Q2M3G0
- Uniprot Name
- ATP-binding cassette sub-family B member 5
- Molecular Weight
- 138639.48 Da
Drug created at October 20, 2016 20:40 / Updated at August 13, 2021 04:44