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Identification
NameDarifenacin
Accession NumberDB00496  (APRD00903)
TypeSmall Molecule
GroupsApproved, Investigational
Description

Darifenacin (Enablex®, Novartis) is a medication used to treat urinary incontinence.

Darifenacin works by blocking the M3 muscarinic acetylcholine receptor, which is primarily responsible for bladder muscle contractions. It thereby decreases the urgency to urinate. It should not be used in people with urinary retention.

It is not known whether this selectivity for the M3 receptor translates into any clinical advantage when treating symptoms of overactive bladder syndrome.

Structure
Thumb
Synonyms
(S)-1-(2-(2,3-dihydro-5-Benzofuranyl)ethyl)-alpha,alpha-diphenyl-3-pyrrolidineacetamide
Darifenacin
Darifenacina
Darifénacine
Darifenacinum
External Identifiers
  • UK 88525
  • UK 88525-04
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Darifenacintablet, extended release15 mg/1oralActavis Pharma, Inc.2016-03-15Not applicableUs
Darifenacintablet, extended release7.5 mg/1oralActavis Pharma, Inc.2016-03-15Not applicableUs
Enablextablet, extended release7.5 mg/1oralWarner Chilcott (US), LLC2004-12-22Not applicableUs
Enablextablet, extended release7.5 mg/1oralPhysicians Total Care, Inc.2006-11-06Not applicableUs
Enablextablet, extended release15 mg/1oralPhysicians Total Care, Inc.2005-07-20Not applicableUs
Enablextablet, extended release15 mg/1oralLake Erie Medical & Surgical Supply DBA Quality Care Products LLC2012-03-05Not applicableUs
Enablextablet (extended-release)15 mgoralMerus Labs Luxco S. A R.L.2006-04-06Not applicableCanada
Enablextablet, extended release15 mg/1oralWarner Chilcott (US), LLC2004-12-22Not applicableUs
Enablextablet (extended-release)7.5 mgoralMerus Labs Luxco S. A R.L.2006-04-06Not applicableCanada
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Darifenacin Hydrobromide Extended-releasetablet, extended release7.5 mg/1oralPar Pharmaceutical2016-03-15Not applicableUs
Darifenacin Hydrobromide Extended-releasetablet, extended release15 mg/1oralPar Pharmaceutical2016-03-15Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
EmselexNovartis
XelenaDr. Reddy's
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Darifenacin Hydrobromide
ThumbNot applicableDBSALT001041
Categories
UNIIAPG9819VLM
CAS number133099-04-4
WeightAverage: 426.55
Monoisotopic: 426.230728214
Chemical FormulaC28H30N2O2
InChI KeyInChIKey=HXGBXQDTNZMWGS-RUZDIDTESA-N
InChI
InChI=1S/C28H30N2O2/c29-27(31)28(23-7-3-1-4-8-23,24-9-5-2-6-10-24)25-14-17-30(20-25)16-13-21-11-12-26-22(19-21)15-18-32-26/h1-12,19,25H,13-18,20H2,(H2,29,31)/t25-/m1/s1
IUPAC Name
2-[(3S)-1-[2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]pyrrolidin-3-yl]-2,2-diphenylacetamide
SMILES
NC(=O)C([C@@H]1CCN(CCC2=CC3=C(OCC3)C=C2)C1)(C1=CC=CC=C1)C1=CC=CC=C1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassDiphenylmethanes
Direct ParentDiphenylmethanes
Alternative Parents
Substituents
  • Diphenylmethane
  • Phenylacetamide
  • Phenylpropylamine
  • Phenethylamine
  • Benzofuran
  • Aralkylamine
  • Alkyl aryl ether
  • N-alkylpyrrolidine
  • Pyrrolidine
  • Tertiary aliphatic amine
  • Tertiary amine
  • Primary carboxylic acid amide
  • Carboxamide group
  • Oxacycle
  • Azacycle
  • Organoheterocyclic compound
  • Ether
  • Carboxylic acid derivative
  • Carboxylic acid amide
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationFor the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency.
PharmacodynamicsDarifenacin is a competitive muscarinic receptor antagonist. In vitro studies using human recombinant muscarinic receptor subtypes show that darifenacin has greater affinity for the M3 receptor than for the other known muscarinic receptors (9 and 12-fold greater affinity for M3 compared to M1 and M5, respectively, and 59-fold greater affinity for M3 compared to both M2 and M4). Muscarinic receptors play an important role in several major cholinergically mediated functions, including contractions of the urinary bladder smooth muscle and stimulation of salivary secretion. Adverse drug effects such as dry mouth, constipation and abnormal vision may be mediated through effects on M3 receptors in these organs.
Mechanism of actionDarifenacin selectively antagonizes the muscarinic M3 receptor. M3 receptors are involved in contraction of human bladder and gastrointestinal smooth muscle, saliva production, and iris sphincter function.
Related Articles
AbsorptionThe mean oral bioavailability at steady state is estimated to be 15% and 19% for 7.5 mg and 15 mg tablets, respectively.
Volume of distribution
  • 163 L
Protein bindingDarifenacin is approximately 98% bound to plasma proteins (primarily to alpha-1-acid-glycoprotein).
Metabolism

Hepatic. Primarily mediated by the cytochrome P450 enzymes CYP2D6 and CYP3A4.

Route of eliminationNot Available
Half lifeThe elimination half-life of darifenacin following chronic dosing is approximately 13-19 hours.
Clearance
  • 40 L/h [extensive metabolizers]
  • 32 L/h [poor metabolizers]
ToxicityOverdosage can potentially result in severe central anticholinergic effects.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9966
Blood Brain Barrier+0.9989
Caco-2 permeable-0.5256
P-glycoprotein substrateSubstrate0.6385
P-glycoprotein inhibitor INon-inhibitor0.6329
P-glycoprotein inhibitor IIInhibitor0.5374
Renal organic cation transporterInhibitor0.6441
CYP450 2C9 substrateNon-substrate0.8774
CYP450 2D6 substrateNon-substrate0.5946
CYP450 3A4 substrateSubstrate0.6046
CYP450 1A2 substrateNon-inhibitor0.696
CYP450 2C9 inhibitorNon-inhibitor0.8253
CYP450 2D6 inhibitorInhibitor0.5816
CYP450 2C19 inhibitorInhibitor0.5399
CYP450 3A4 inhibitorInhibitor0.5
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6168
Ames testNon AMES toxic0.7145
CarcinogenicityNon-carcinogens0.8847
BiodegradationNot ready biodegradable0.9599
Rat acute toxicity3.0008 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.907
hERG inhibition (predictor II)Inhibitor0.6703
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Novartis pharmaceuticals corp
Packagers
Dosage forms
FormRouteStrength
Tablet (extended-release)oral15 mg
Tablet (extended-release)oral7.5 mg
Tablet, extended releaseoral15 mg/1
Tablet, extended releaseoral7.5 mg/1
Prices
Unit descriptionCostUnit
Enablex 15 mg 24 Hour tablet5.22USD tablet
Enablex 7.5 mg 24 Hour tablet5.22USD tablet
Enablex 15 mg tablet5.02USD tablet
Enablex 7.5 mg tablet5.02USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2230314 No2003-06-242016-08-21Canada
CA2469702 No2010-07-062022-03-05Canada
US5096890 No1995-03-132015-03-13Us
US6106864 No1996-08-212016-08-21Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
logP4.5Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.000298 mg/mLALOGPS
logP4.35ALOGPS
logP4.54ChemAxon
logS-6.2ALOGPS
pKa (Strongest Acidic)16.21ChemAxon
pKa (Strongest Basic)10.11ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area55.56 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity128.37 m3·mol-1ChemAxon
Polarizability48.54 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
References
Synthesis Reference

Valeriano Merli, Augusto Canavesi, Paola Daverio, “Processes for preparing darifenacin hydrobromide.” U.S. Patent US20070197631, issued August 23, 2007.

US20070197631
General ReferencesNot Available
External Links
ATC CodesG04BD10
AHFS Codes
  • 86:12.00
PDB EntriesNot Available
FDA labelDownload (394 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AclidiniumAclidinium may increase the anticholinergic activities of Darifenacin.
AprepitantThe serum concentration of Darifenacin can be increased when it is combined with Aprepitant.
AripiprazoleThe serum concentration of Aripiprazole can be increased when it is combined with Darifenacin.
BexaroteneThe serum concentration of Darifenacin can be decreased when it is combined with Bexarotene.
BosentanThe serum concentration of Darifenacin can be decreased when it is combined with Bosentan.
Botulinum Toxin Type ADarifenacin may increase the anticholinergic activities of Botulinum Toxin Type A.
Botulinum Toxin Type BDarifenacin may increase the anticholinergic activities of Botulinum Toxin Type B.
BrexpiprazoleThe serum concentration of Brexpiprazole can be increased when it is combined with Darifenacin.
CimetropiumDarifenacin may increase the anticholinergic activities of Cimetropium Bromide.
CodeineThe therapeutic efficacy of Codeine can be decreased when used in combination with Darifenacin.
ConivaptanThe serum concentration of Darifenacin can be increased when it is combined with Conivaptan.
DabrafenibThe serum concentration of Darifenacin can be decreased when it is combined with Dabrafenib.
DasatinibThe serum concentration of Darifenacin can be increased when it is combined with Dasatinib.
DeferasiroxThe serum concentration of Darifenacin can be decreased when it is combined with Deferasirox.
DoxorubicinThe serum concentration of Doxorubicin can be increased when it is combined with Darifenacin.
DronabinolDarifenacin may increase the tachycardic activities of Dronabinol.
EliglustatThe serum concentration of Eliglustat can be increased when it is combined with Darifenacin.
EluxadolineDarifenacin may increase the activities of Eluxadoline.
FesoterodineThe serum concentration of the active metabolites of Fesoterodine can be increased when Fesoterodine is used in combination with Darifenacin.
FluconazoleThe metabolism of Darifenacin can be decreased when combined with Fluconazole.
FluvoxamineThe metabolism of Fluvoxamine can be decreased when combined with Darifenacin.
FosaprepitantThe serum concentration of Darifenacin can be increased when it is combined with Fosaprepitant.
Fusidic AcidThe serum concentration of Darifenacin can be increased when it is combined with Fusidic Acid.
Glucagon recombinantThe risk or severity of adverse effects can be increased when Darifenacin is combined with Glucagon recombinant.
IdelalisibThe serum concentration of Darifenacin can be increased when it is combined with Idelalisib.
Ipratropium bromideIpratropium bromide may increase the anticholinergic activities of Darifenacin.
ItoprideThe therapeutic efficacy of Itopride can be decreased when used in combination with Darifenacin.
IvacaftorThe serum concentration of Darifenacin can be increased when it is combined with Ivacaftor.
LuliconazoleThe serum concentration of Darifenacin can be increased when it is combined with Luliconazole.
MetoprololThe serum concentration of Metoprolol can be increased when it is combined with Darifenacin.
MianserinMianserin may increase the anticholinergic activities of Darifenacin.
MifepristoneThe serum concentration of Darifenacin can be increased when it is combined with Mifepristone.
MirabegronThe risk or severity of adverse effects can be increased when Darifenacin is combined with Mirabegron.
MitotaneThe serum concentration of Darifenacin can be decreased when it is combined with Mitotane.
MorphineThe risk or severity of adverse effects can be increased when Darifenacin is combined with Morphine.
NebivololThe serum concentration of Nebivolol can be increased when it is combined with Darifenacin.
NelfinavirThe metabolism of Darifenacin can be decreased when combined with Nelfinavir.
NetupitantThe serum concentration of Darifenacin can be increased when it is combined with Netupitant.
PalbociclibThe serum concentration of Darifenacin can be increased when it is combined with Palbociclib.
PhenytoinThe metabolism of Darifenacin can be increased when combined with Phenytoin.
Potassium ChlorideDarifenacin may increase the ulcerogenic activities of Potassium Chloride.
PramlintidePramlintide may increase the anticholinergic activities of Darifenacin.
ProcyclidineThe risk or severity of adverse effects can be increased when Procyclidine is combined with Darifenacin.
PropafenoneThe serum concentration of Darifenacin can be increased when it is combined with Propafenone.
RamosetronDarifenacin may increase the activities of Ramosetron.
SecretinThe therapeutic efficacy of Secretin can be decreased when used in combination with Darifenacin.
SiltuximabThe serum concentration of Darifenacin can be decreased when it is combined with Siltuximab.
SimeprevirThe serum concentration of Darifenacin can be increased when it is combined with Simeprevir.
St. John's WortThe serum concentration of Darifenacin can be decreased when it is combined with St. John's Wort.
StiripentolThe serum concentration of Darifenacin can be increased when it is combined with Stiripentol.
SulpirideThe therapeutic efficacy of Sulpiride can be decreased when used in combination with Darifenacin.
TacrineThe therapeutic efficacy of Darifenacin can be decreased when used in combination with Tacrine.
TamoxifenThe serum concentration of the active metabolites of Tamoxifen can be reduced when Tamoxifen is used in combination with Darifenacin resulting in a loss in efficacy.
ThioridazineThe serum concentration of Thioridazine can be increased when it is combined with Darifenacin.
TiotropiumDarifenacin may increase the anticholinergic activities of Tiotropium.
TocilizumabThe serum concentration of Darifenacin can be decreased when it is combined with Tocilizumab.
TopiramateThe risk or severity of adverse effects can be increased when Darifenacin is combined with Topiramate.
TramadolThe therapeutic efficacy of Tramadol can be decreased when used in combination with Darifenacin.
TrichlormethiazideThe serum concentration of Trichlormethiazide can be increased when it is combined with Darifenacin.
UmeclidiniumUmeclidinium may increase the anticholinergic activities of Darifenacin.
Food Interactions
  • Take without regard to meals.

Targets

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 action of G proteins. Primary transducing effect is Pi turnover.
Gene Name:
CHRM3
Uniprot ID:
P20309
Molecular Weight:
66127.445 Da
References
  1. Bharucha AE, Ravi K, Zinsmeister AR: Comparison of selective M3 and nonselective muscarinic receptor antagonists on gastrointestinal transit and bowel habits in humans. Am J Physiol Gastrointest Liver Physiol. 2010 Jul;299(1):G215-9. doi: 10.1152/ajpgi.00072.2010. Epub 2010 Apr 15. [PubMed:20395537 ]
  2. Bozkurt TE, Sahin-Erdemli I: M(1) and M(3) muscarinic receptors are involved in the release of urinary bladder-derived relaxant factor. Pharmacol Res. 2009 May;59(5):300-5. doi: 10.1016/j.phrs.2009.01.013. Epub 2009 Feb 5. [PubMed:19416629 ]
  3. Jha S, Parsons M: Treatment of overactive bladder in the aging population: focus on darifenacin. Clin Interv Aging. 2006;1(4):309-16. [PubMed:18046909 ]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
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 action of G proteins. Primary transducing effect is Pi turnover.
Gene Name:
CHRM1
Uniprot ID:
P11229
Molecular Weight:
51420.375 Da
References
  1. Jha S, Parsons M: Treatment of overactive bladder in the aging population: focus on darifenacin. Clin Interv Aging. 2006;1(4):309-16. [PubMed:18046909 ]
  2. Moriya H, Takagi Y, Nakanishi T, Hayashi M, Tani T, Hirotsu I: Affinity profiles of various muscarinic antagonists for cloned human muscarinic acetylcholine receptor (mAChR) subtypes and mAChRs in rat heart and submandibular gland. Life Sci. 1999;64(25):2351-8. [PubMed:10374898 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
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 action of G proteins. Primary transducing effect is adenylate cyclase inhibition. Signaling promotes phospholipase C activity, leading to the release of inositol trisphosphate (IP3); this then trigge...
Gene Name:
CHRM2
Uniprot ID:
P08172
Molecular Weight:
51714.605 Da
References
  1. Jha S, Parsons M: Treatment of overactive bladder in the aging population: focus on darifenacin. Clin Interv Aging. 2006;1(4):309-16. [PubMed:18046909 ]
  2. Moriya H, Takagi Y, Nakanishi T, Hayashi M, Tani T, Hirotsu I: Affinity profiles of various muscarinic antagonists for cloned human muscarinic acetylcholine receptor (mAChR) subtypes and mAChRs in rat heart and submandibular gland. Life Sci. 1999;64(25):2351-8. [PubMed:10374898 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
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 action of G proteins. Primary transducing effect is inhibition of adenylate cyclase.
Gene Name:
CHRM4
Uniprot ID:
P08173
Molecular Weight:
53048.65 Da
References
  1. Jha S, Parsons M: Treatment of overactive bladder in the aging population: focus on darifenacin. Clin Interv Aging. 2006;1(4):309-16. [PubMed:18046909 ]
  2. Moriya H, Takagi Y, Nakanishi T, Hayashi M, Tani T, Hirotsu I: Affinity profiles of various muscarinic antagonists for cloned human muscarinic acetylcholine receptor (mAChR) subtypes and mAChRs in rat heart and submandibular gland. Life Sci. 1999;64(25):2351-8. [PubMed:10374898 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
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 action of G proteins. Primary transducing effect is Pi turnover.
Gene Name:
CHRM5
Uniprot ID:
P08912
Molecular Weight:
60073.205 Da
References
  1. Moriya H, Takagi Y, Nakanishi T, Hayashi M, Tani T, Hirotsu I: Affinity profiles of various muscarinic antagonists for cloned human muscarinic acetylcholine receptor (mAChR) subtypes and mAChRs in rat heart and submandibular gland. Life Sci. 1999;64(25):2351-8. [PubMed:10374898 ]
  2. Jha S, Parsons M: Treatment of overactive bladder in the aging population: focus on darifenacin. Clin Interv Aging. 2006;1(4):309-16. [PubMed:18046909 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
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 reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. Skerjanec A: The clinical pharmacokinetics of darifenacin. Clin Pharmacokinet. 2006;45(4):325-50. [PubMed:16584282 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
General Function:
Steroid hydroxylase activity
Specific Function:
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.
Gene Name:
CYP2D6
Uniprot ID:
P10635
Molecular Weight:
55768.94 Da
References
  1. Skerjanec A: The clinical pharmacokinetics of darifenacin. Clin Pharmacokinet. 2006;45(4):325-50. [PubMed:16584282 ]
Comments
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Drug created on June 13, 2005 07:24 / Updated on August 24, 2016 01:52