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Identification
Name Fesoterodine
Accession Number DB06702
Type small molecule
Groups approved
Description

Fesoterodine is an antimuscarinic prodrug for the treatment of overactive bladder syndrome.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
FESO
Salts
  • Fesoterodine Fumarate
Brand names
Name Company
Toviaz Pfizer
Brand mixtures Not Available
Categories
  • Antispasmodics
  • Anti-Incontinence Agents
  • Antimuscarinics
  • Genitourinary Smooth Muscle Relaxants
CAS number 286930-03-8
Weight Average: 411.5769
Monoisotopic: 411.277344055
Chemical Formula C26H37NO3
InChI Key InChIKey=DCCSDBARQIPTGU-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
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Diphenylmethanes
Substructures
  • Carboxylic Acids and Derivatives
  • Hydroxy Compounds
  • Benzyl Alcohols and Derivatives
  • Acetates
  • Phenols and Derivatives
  • Phenylacetates
  • Ethers
  • Benzene and Derivatives
  • Alcohols and Polyols
  • Aliphatic and Aryl Amines
  • Diphenylmethanes
  • Aromatic compounds
  • Anisoles
  • Phenylpropylamines
  • Phenyl Esters
Pharmacology
Indication For the treatment of overactive bladder (with symptoms of urinary frequency, urgency, or urge incontinence).
Pharmacodynamics Fesoterodine 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 action Fesoterodine, 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.
Absorption Tmax (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 binding 5-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 elimination Renal: 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 life 7-8 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.
Toxicity Rat, 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
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Pfizer inc
Packagers Not Available
Dosage forms
Form Route Strength
Tablet Oral 4 mg
Tablet Oral 8 mg
Prices Not Available
Patents
Country Patent Number Approved Expires (estimated)
United States 7384980 1999-10-14 2019-10-14
United States 6858650 1999-05-11 2019-05-11
Properties
State solid
Experimental Properties
Property Value Source
water solubility Highly soluble MSDS
Predicted Properties
Property Value Source
water solubility 2.05e-03 g/l ALOGPS
logP 5.45 ALOGPS
logP 5.7 ChemAxon
logS -5.3 ALOGPS
pKa (strongest acidic) 14.98 ChemAxon
pKa (strongest basic) 10.64 ChemAxon
physiological charge 1 ChemAxon
hydrogen acceptor count 3 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 49.77 ChemAxon
rotatable bond count 11 ChemAxon
refractivity 124.08 ChemAxon
polarizability 48.29 ChemAxon
References
Synthesis Reference Not Available
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
Resource Link
KEGG Drug D07226 Link_out
PubChem Compound 6918558 Link_out
PubChem Substance 99443256 Link_out
ChemSpider 5293755 Link_out
PharmGKB PA165958376 Link_out
RxList http://www.rxlist.com/toviaz-drug.htm Link_out
Drugs.com http://www.drugs.com/cdi/fesoterodine.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Fesoterodine Link_out
ATC Codes
  • G04BD11
AHFS Codes
  • 12:08.08
PDB Entries Not Available
FDA label show (430 KB)
MSDS show (102 KB)
Interactions
Drug Interactions
Drug Interaction
Conivaptan CYP3A4 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.
Fluconazole Fluconazole is a moderate CYP3A4 inhibitor thus reducing clearance. Monitor for adverse effects when using concomitant therapy with fesoterodine.
Ketoconazole Ketoconazole 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

Pharmacological action: yes
Actions: antagonist

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

Organism class: human
UniProt ID: P20309 Link_out
Gene: CHRM3 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: unknown
Actions: antagonist

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

Organism class: human
UniProt ID: P08173 Link_out
Gene: CHRM4 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: unknown
Actions: antagonist

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

Organism class: human
UniProt ID: P11229 Link_out
Gene: CHRM1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: unknown
Actions: antagonist

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

Organism class: human
UniProt ID: P08172 Link_out
Gene: CHRM2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: unknown
Actions: antagonist

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

Organism class: human
UniProt ID: P08912 Link_out
Gene: CHRM5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

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 xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

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

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Comments
Drug created on May 06, 2010 10:47 / Updated on March 24, 2013 21:08