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Identification
NameFesoterodine
Accession NumberDB06702
Typesmall molecule
Groupsapproved
Description

Fesoterodine is an antimuscarinic prodrug for the treatment of overactive bladder syndrome.

Structure
Thumb
Synonyms
SynonymLanguageCode
FESONot AvailableNot Available
FesoterodineNot AvailableNot Available
Salts
Name/CAS Structure Properties
Fesoterodine Fumarate
Thumb
  • InChI Key: MWHXMIASLKXGBU-RNCYCKTQSA-N
  • Monoisotopic Mass: 527.288302671
  • Average Mass: 527.649
DBSALT000085
Brand names
NameCompany
ToviazPfizer
Brand mixturesNot Available
Categories
CAS number286930-03-8
WeightAverage: 411.5769
Monoisotopic: 411.277344055
Chemical FormulaC26H37NO3
InChI KeyDCCSDBARQIPTGU-HSZRJFAPSA-N
InChI
InChI=1S/C26H37NO3/c1-18(2)26(29)30-25-13-12-21(17-28)16-24(25)23(22-10-8-7-9-11-22)14-15-27(19(3)4)20(5)6/h7-13,16,18-20,23,28H,14-15,17H2,1-6H3/t23-/m1/s1
IUPAC Name
2-[(1R)-3-[bis(propan-2-yl)amino]-1-phenylpropyl]-4-(hydroxymethyl)phenyl 2-methylpropanoate
SMILES
CC(C)N(CC[C@H](C1=CC=CC=C1)C1=C(OC(=O)C(C)C)C=CC(CO)=C1)C(C)C
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassDiphenylmethanes
Direct parentDiphenylmethanes
Alternative parentsPhenylpropylamines; Phenol Esters; Phenol Ethers; Alkyl Aryl Ethers; Tertiary Amines; Carboxylic Acid Esters; Enolates; Primary Alcohols; Polyamines
Substituentsphenol ester; phenylpropylamine; phenol ether; alkyl aryl ether; carboxylic acid ester; tertiary amine; primary alcohol; enolate; carboxylic acid derivative; polyamine; ether; amine; alcohol; organonitrogen compound
Classification descriptionThis compound belongs to the diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
Pharmacology
IndicationFor the treatment of overactive bladder (with symptoms of urinary frequency, urgency, or urge incontinence).
PharmacodynamicsFesoterodine is a prodrug. In-vivo it is broken down into its active metabolite, 5-hydroxymethyl tolterodine (5-HMT), by plasma esterases. The 5-hydroxymethyl metabolite, which exhibits an antimuscarinic activity. Both urinary bladder contraction and salivation are mediated via cholinergic muscarinic receptors. Therefore, acting as a competitive muscarinic receptor antagonist, fesoterodine ultimately acts to decrease the detrusor pressure by its muscarinic antagonism, thereby decreasing bladder contraction and consequently, the urge to urinate.
Mechanism of actionFesoterodine, once converted to its active metabolite, 5-hydroxymethyltolterodine, acts as a competitive antagonists at muscarinic receptors. This results in the inhibition of bladder contraction, decrease in detrusor pressure, and an incomplete emptying of the bladder.
AbsorptionTmax (5-HMT): 5 hours post-adminitration of fesoterodine. AUC (0,∞)= 49.5 ng·h/ ml Bioavailability, 5-HMT = 52%
Volume of distribution

IV, 5-HMT: 169 L

Protein binding5-HMT: 50% to albumin and alpha1-acid glycoprotein
Metabolism

Metabolized by ubiquitous, nonspecific esterases to transform fesoterodine into 5-HMT Extensive metabolism via CYP2D6 and CYP3A4 into inactive metabolites

Route of eliminationRenal: 70% of fesoterodine was recovered in urine as 5-HMT; 35% carboxy metabolite; 18% carboxy-N-desisopropylmetabolite, and 1% N-desisopropyl metabolite Fecal: 7% Hepatic: fesoterodine elimination via CYP2D6 and CYP3A4
Half life7-8 hours for the active metabolite 5-hydroxymethyl tolterodine
Clearance

5-HMT, healthy subjects: 14.4 L/h
5-HMT is also secreted into the nephron.

ToxicityRat, Oral, LD50: ~ 681 mg/kg Mouse, Oral, LD50: ~ 316 mg/kg Rat, Intravenous, NOAEL: 10 mg/kg Mouse, Intravenous, NOAEL: 10 mg/kg
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9535
Blood Brain Barrier + 0.5648
Caco-2 permeable + 0.7699
P-glycoprotein substrate Substrate 0.5268
P-glycoprotein inhibitor I Non-inhibitor 0.5556
P-glycoprotein inhibitor II Non-inhibitor 0.625
Renal organic cation transporter Inhibitor 0.6025
CYP450 2C9 substrate Non-substrate 0.6853
CYP450 2D6 substrate Non-substrate 0.5151
CYP450 3A4 substrate Substrate 0.5939
CYP450 1A2 substrate Inhibitor 0.6306
CYP450 2C9 substrate Non-inhibitor 0.7227
CYP450 2D6 substrate Inhibitor 0.6255
CYP450 2C19 substrate Non-inhibitor 0.7334
CYP450 3A4 substrate Non-inhibitor 0.5718
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.6144
Ames test Non AMES toxic 0.646
Carcinogenicity Non-carcinogens 0.7213
Biodegradation Not ready biodegradable 0.9385
Rat acute toxicity 2.4003 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9196
hERG inhibition (predictor II) Inhibitor 0.5602
Pharmacoeconomics
Manufacturers
  • Pfizer inc
PackagersNot Available
Dosage forms
FormRouteStrength
TabletOral4 mg
TabletOral8 mg
PricesNot Available
Patents
CountryPatent NumberApprovedExpires (estimated)
United States73849801999-10-142019-10-14
United States68586501999-05-112019-05-11
Properties
Statesolid
Experimental Properties
PropertyValueSource
water solubilityHighly soluble MSDS
Predicted Properties
PropertyValueSource
water solubility2.05e-03 g/lALOGPS
logP5.45ALOGPS
logP5.7ChemAxon
logS-5.3ALOGPS
pKa (strongest acidic)14.98ChemAxon
pKa (strongest basic)10.64ChemAxon
physiological charge1ChemAxon
hydrogen acceptor count3ChemAxon
hydrogen donor count1ChemAxon
polar surface area49.77ChemAxon
rotatable bond count11ChemAxon
refractivity124.08ChemAxon
polarizability48.29ChemAxon
number of rings2ChemAxon
bioavailability0ChemAxon
rule of fiveNoChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Claus Meese, “CHIRAL INTERMEDIATE, PROCESS FOR PRODUCING THE SAME AND ITS USE IN THE MANUFACTURE OF TOLTERODINE, FESOTERODINE, OR THE ACTIVE METABOLITE THEREOF.” U.S. Patent US20090192224, issued July 30, 2009.

US20090192224
General Reference
  1. Malhotra B, Dickins M, Alvey C, Jumadilova Z, Li X, Duczynski G, Gandelman K: Effects of the moderate CYP3A4 inhibitor, fluconazole, on the pharmacokinetics of fesoterodine in healthy subjects. Br J Clin Pharmacol. 2011 Aug;72(2):263-9. doi: 10.1111/j.1365-2125.2011.04007.×. Pubmed
  2. Malhotra B, Gandelman K, Sachse R, Wood N, Michel MC: The design and development of fesoterodine as a prodrug of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of tolterodine. Curr Med Chem. 2009;16(33):4481-9. Pubmed
External Links
ResourceLink
KEGG DrugD07226
PubChem Compound6918558
PubChem Substance99443256
ChemSpider5293755
PharmGKBPA165958376
RxListhttp://www.rxlist.com/toviaz-drug.htm
Drugs.comhttp://www.drugs.com/cdi/fesoterodine.html
WikipediaFesoterodine
ATC CodesG04BD11
AHFS Codes
  • 12:08.08
PDB EntriesNot Available
FDA labelshow(430 KB)
MSDSshow(102 KB)
Interactions
Drug Interactions
Drug
ConivaptanCYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fesoterodine. Avoid fesoterodine doses greater than 4mg daily in patients who are also receiving strong CYP3A4 inhibitors.
FluconazoleFluconazole is a moderate CYP3A4 inhibitor thus reducing clearance. Monitor for adverse effects when using concomitant therapy with fesoterodine.
KetoconazoleKetoconazole is a potent CYP3A4 inhibitor thus reducing clearance. Avoid concomitant use with fesoterodine.
Food Interactions
  • Take with or without food.

Targets

1. Muscarinic acetylcholine receptor M3

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Muscarinic acetylcholine receptor M3 P20309 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Nilvebrant L: Tolterodine and its active 5-hydroxymethyl metabolite: pure muscarinic receptor antagonists. Pharmacol Toxicol. 2002 May;90(5):260-7. Pubmed

2. Muscarinic acetylcholine receptor M4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: antagonist

Components

Name UniProt ID Details
Muscarinic acetylcholine receptor M4 P08173 Details

References:

  1. Mansfield KJ, Chandran JJ, Vaux KJ, Millard RJ, Christopoulos A, Mitchelson FJ, Burcher E: Comparison of receptor binding characteristics of commonly used muscarinic antagonists in human bladder detrusor and mucosa. J Pharmacol Exp Ther. 2009 Mar;328(3):893-9. Epub 2008 Nov 24. Pubmed

3. Muscarinic acetylcholine receptor M1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: antagonist

Components

Name UniProt ID Details
Muscarinic acetylcholine receptor M1 P11229 Details

References:

  1. Nilvebrant L: Tolterodine and its active 5-hydroxymethyl metabolite: pure muscarinic receptor antagonists. Pharmacol Toxicol. 2002 May;90(5):260-7. Pubmed

4. Muscarinic acetylcholine receptor M2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: antagonist

Components

Name UniProt ID Details
Muscarinic acetylcholine receptor M2 P08172 Details

References:

  1. Mansfield KJ, Chandran JJ, Vaux KJ, Millard RJ, Christopoulos A, Mitchelson FJ, Burcher E: Comparison of receptor binding characteristics of commonly used muscarinic antagonists in human bladder detrusor and mucosa. J Pharmacol Exp Ther. 2009 Mar;328(3):893-9. Epub 2008 Nov 24. Pubmed

5. Muscarinic acetylcholine receptor M5

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: antagonist

Components

Name UniProt ID Details
Muscarinic acetylcholine receptor M5 P08912 Details

References:

  1. Mansfield KJ, Chandran JJ, Vaux KJ, Millard RJ, Christopoulos A, Mitchelson FJ, Burcher E: Comparison of receptor binding characteristics of commonly used muscarinic antagonists in human bladder detrusor and mucosa. J Pharmacol Exp Ther. 2009 Mar;328(3):893-9. Epub 2008 Nov 24. Pubmed

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Malhotra B, Guan Z, Wood N, Gandelman K: Pharmacokinetic profile of fesoterodine. Int J Clin Pharmacol Ther. 2008 Nov;46(11):556-63. Pubmed
  2. Malhotra B, Dickins M, Alvey C, Jumadilova Z, Li X, Duczynski G, Gandelman K: Effects of the Moderate CYP3A4 Inhibitor, Fluconazole, on the Pharmacokinetics of Fesoterodine in Healthy Subjects. Br J Clin Pharmacol. 2011 May 5. doi: 10.1111/j.1365-2125.2011.04007.×. Pubmed
  3. Malhotra B, Sachse R, Wood N: Evaluation of drug-drug interactions with fesoterodine. Eur J Clin Pharmacol. 2009 Jun;65(6):551-60. Epub 2009 Apr 4. Pubmed
  4. Malhotra BK, Wood N, Sachse R: Influence of age, gender, and race on pharmacokinetics, pharmacodynamics, and safety of fesoterodine. Int J Clin Pharmacol Ther. 2009 Sep;47(9):570-8. Pubmed

2. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

References:

  1. Malhotra B, Guan Z, Wood N, Gandelman K: Pharmacokinetic profile of fesoterodine. Int J Clin Pharmacol Ther. 2008 Nov;46(11):556-63. Pubmed
  2. Malhotra B, Dickins M, Alvey C, Jumadilova Z, Li X, Duczynski G, Gandelman K: Effects of the Moderate CYP3A4 Inhibitor, Fluconazole, on the Pharmacokinetics of Fesoterodine in Healthy Subjects. Br J Clin Pharmacol. 2011 May 5. doi: 10.1111/j.1365-2125.2011.04007.×. Pubmed
  3. Malhotra B, Sachse R, Wood N: Evaluation of drug-drug interactions with fesoterodine. Eur J Clin Pharmacol. 2009 Jun;65(6):551-60. Epub 2009 Apr 4. Pubmed
  4. Malhotra BK, Wood N, Sachse R: Influence of age, gender, and race on pharmacokinetics, pharmacodynamics, and safety of fesoterodine. Int J Clin Pharmacol Ther. 2009 Sep;47(9):570-8. Pubmed

Transporters

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. Chancellor MB, Staskin DR, Kay GG, Sandage BW, Oefelein MG, Tsao JW: Blood-brain barrier permeation and efflux exclusion of anticholinergics used in the treatment of overactive bladder. Drugs Aging. 2012 Apr 1;29(4):259-73. doi: 10.2165/11597530-000000000-00000. Pubmed

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Drug created on May 06, 2010 10:47 / Updated on September 16, 2013 18:04