Fesoterodine targets muscarinic acetylcholine receptors (mAChRs). It has pKi values of 8.0, 7.7, 7.4, 7.3, and 7.5 for M1, M2, M3, M4, and M5 receptors, respectively. The active metabolite 5-HMT binds and inhibits muscarinic receptors on the bladder detrusor muscle, thereby preventing bladder contractions or spasms caused by acetylcholine.

Fesoterodine increases the volume of pee produced during a urination while decreasing the frequency, intensity, and duration of urge urinary incontinence episodes [1]. Following oral ingestion, non-specific esterases quickly and thoroughly hydrolyze fesoterodine in plasma to produce Desfesoterodine (5-hydroxymethyl tolterodine; SPM 7605; fesoterodine's active metabolite) [3][4].
In vitro, fesoterodine is a competitive muscarinic receptor antagonist. It has pKi values of 8.0, 7.7, 7.4, 7.3, and 7.5 for M1, M2, M3, M4, and M5 receptors, respectively. It decreases micturition frequency, urgency severity, and urgency incontinence episodes and increases the volume voided with each micturition. Its activity is assessed in receptor binding and functional assays.

Fesoterodine (0.01-1 mg/kg; intravenously) lowers micturition pressure and increases bladder capacity and ICI (intercontraction interval) at the lowest dose studied, 0.01 mg/kg [3].
In vivo, fesoterodine is an orally active prodrug that is rapidly converted to its active metabolite 5-HMT. The recommended starting dose is 4 mg once daily, and the dose may be increased to 8 mg once daily. It is used for the treatment of overactive bladder syndrome. It decreases micturition frequency and urgency severity.

The in vitro receptor binding assay for fesoterodine measures its affinity for muscarinic acetylcholine receptors. Radioligand binding studies are performed using membrane preparations from cells expressing human M1-M5 receptors. The compound's ability to compete with a radiolabeled muscarinic antagonist is measured, and pKi values are calculated. Functional assays measure the inhibition of agonist-induced calcium mobilization.

In vitro cellular studies are conducted using cell lines expressing muscarinic receptors. Cells are treated with fesoterodine or its active metabolite 5-HMT. Receptor binding affinity is measured. Functional antagonism is assessed by measuring the inhibition of agonist-induced intracellular calcium mobilization or other downstream signaling pathways. The compound's effects on bladder smooth muscle contraction are studied in isolated tissue preparations.

Animal/Disease Models: Female SD (SD (Sprague-Dawley)) rat bladder (225-275 g) [3]
Doses: 0.01, 0.1 and 1 mg/kg
Route of Administration: intravenous (iv) (iv)injection
Experimental Results: At the lowest dose tested, micturition pressure diminished, bladder Capacity and ICI increased by 0.01 mg/kg.
In vivo animal experiments are performed in models of overactive bladder. Animals are administered fesoterodine via oral gavage or intravenous injection. Bladder function is assessed by cystometry or by measuring micturition frequency and volume. The compound's effects on bladder contractions and urinary incontinence are evaluated. Pharmacokinetic studies measure the conversion to the active metabolite 5-HMT.

Absorption, Distribution and Excretion
Tmax (5-HMT): 5 hours after administration of fesotropin. AUC (0,∞) = 49.5 ng·h/ml. Bioavailability, 5-HMT = 52%. Kidney: 70% of fesotropin is recovered in urine as 5-HMT; 35% as carboxyl metabolites; 18% as carboxyl-N-deisopropyl metabolites; 1% as N-deisopropyl metabolites. Feces: 7%. Liver: Fesotropin is eliminated via metabolism by CYP2D6 and CYP3A4. Intravenous injection, 5-hydroxymethyltolterodine: 169 L. 5-hydroxymethyltolterodine, in healthy subjects: 14.4 L/h. 5-hydroxymethyltolterodine is also secreted into nephrons.

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Metabolism/Metabolites
Fesoterodine is metabolized to 5-hydroxymethyltolterodine by ubiquitous nonspecific esterases. It is extensively metabolized by CYP2D6 and CYP3A4 to inactive metabolites.

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Biological Half-Life
The half-life of the active metabolite 5-hydroxymethyltolterodine is 7-8 hours.
Fesoterodine has a molecular formula and molecular weight consistent with its structure. It is an orally active prodrug. For storage, it should be kept at -20°C, protected from light and moisture. The compound is supplied with high purity for research purposes. It is a competitive muscarinic receptor antagonist with muscle relaxant and urinary antispasmodic properties.

Hepatotoxicity
As with most anticholinergic drugs, fexosteroids have not been reported to be associated with elevated liver enzymes or clinically significant liver injury. In a prospective, randomized, placebo-controlled trial of fexosteroids for overactive bladder, elevated serum transaminases were rare, occurring in less than 1% of cases, similar to the placebo group. Since its approval, there have been no published case reports of clinically significant liver injury caused by fexosteroids. Probability score: E (unlikely to cause clinically significant liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation There is currently no information regarding the use of fexosteroids during lactation. Prolonged use of fexosteroids may reduce milk production or the milk ejection reflex. With prolonged use, signs of reduced milk production (e.g., dissatisfaction, poor weight gain) should be observed. ◉ Effects on Breastfed Infants As of the revision date, no relevant published information was found.
◉ Effects on Lactation and Breast Milk
As of the revision date, no published information was found regarding lactating mothers. Anticholinergic drugs can suppress lactation in animals by inhibiting the secretion of growth hormone and oxytocin. Anticholinergic drugs can also lower serum prolactin levels in non-lactating women. Prolactin levels in established lactating mothers may not affect their ability to breastfeed.

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Protein Binding
5-Hydroxymethyltransferase: 50% bound to albumin and α1-acid glycoprotein

As a therapeutic agent, fesoterodine is generally well-tolerated. Common side effects include dry mouth, constipation, and blurred vision, which are typical of antimuscarinic agents. It is contraindicated in patients with urinary retention, gastric retention, and uncontrolled narrow-angle glaucoma. As a research chemical, standard laboratory safety precautions should be followed.

[1]. Fesoterodine for the treatment of urinary incontinence and overactive bladder. Ther Clin Risk Manag. 2009;5:869-76. Epub 2009 Nov 18.

[2]. The Beneficial Effect of Fesoterodine, a Competitive Muscarinic Receptor Antagonist on Erectile Dysfunction in Streptozotocin-induced Diabetic Rats.

[3]. Pharmacological Characterization of a Novel Investigational Antimuscarinic Drug, Fesoterodine, in Vitro and in Vivo. BJU Int. 2008 Apr;101(8):1036-42.

[4]. Fesoterodine: A Novel Muscarinic Receptor Antagonist for the Treatment of Overactive Bladder Syndrome. Expert Opin Pharmacother. 2008 Jul;9(10):1787-96.

Fesoterodine is a diarylmethane compound. It is an antimuscarinic prodrug used to treat overactive bladder. Fesoterodine is also an anticholinergic and antispasmodic drug used to treat urinary incontinence and overactive bladder. Fesoterodine does not cause elevated liver enzymes or clinically significant acute liver injury. Fesoterodine is a competitive muscarinic receptor antagonist with muscle relaxant and urinary tract antispasmodic effects. In vivo, Fesoterodine is rapidly hydrolyzed to its active metabolite, 5-hydroxymethyltolterodine, which binds to and inhibits the activity of muscarinic receptors on the detrusor muscle of the bladder, thereby preventing acetylcholine-induced bladder contractions or spasms. This relaxes the bladder smooth muscle, increases bladder capacity, and reduces involuntary muscle contractions and involuntary urine leakage. The active metabolite does not interact with α-adrenergic receptors, serotonergic receptors, histamine receptors, or excitatory amino acid receptors and is eliminated through renal excretion. See also: fexordine fumarate (in saline form).

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Drug Indications
Fexordine is indicated for the treatment of overactive bladder in adult patients, including symptoms such as urinary urgency, frequency, and urge incontinence. It is also indicated for the treatment of neurogenic detrusor overactivity in children weighing more than 25 kg and aged ≥6 years.
FDA Label
For the treatment of symptoms that may occur in patients with overactive bladder (urinary frequency and/or urinary urgency and/or urge incontinence).

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Mechanism of Action
After being converted to its active metabolite, 5-hydroxymethyltolterodine, fexordine acts as a competitive antagonist of muscarinic receptors. This results in inhibition of bladder contractions, decreased detrusor pressure, and incomplete bladder emptying.

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Pharmacodynamics
In vivo, the fexordine prodrug is broken down by plasma esterases to the active metabolite, 5-hydroxymethyltolterodine (5-HMT). 5-Hydroxymethyl metabolites possess antimuscarinic activity. Bladder contraction and salivation are both mediated by cholinergic muscarinic receptors. Therefore, as a competitive muscarinic receptor antagonist, fesorodine ultimately reduces detrusor pressure through its muscarinic antagonistic effect, thereby reducing bladder contraction and alleviating urinary urgency.
Fesoterodine is also known by the brand name Toviaz. It is an orally active, nonsubtype selective, competitive muscarinic receptor antagonist. It is a prodrug that is rapidly hydrolyzed in vivo to its active metabolite 5-hydroxy methyl tolterodine. Fesoterodine was approved by the FDA in 2008 for the treatment of overactive bladder syndrome.

C26H37NO3

411.5769

412.285

286930-02-7

Fesoterodine L-mandelate;1206695-46-6;Fesoterodine fumarate;286930-03-8

6918558

Colorless to light yellow viscous liquid

1.043

518.9ºC at 760 mmHg

267.6ºC

5.488

1

4

11

30

491

1

O(C(C([H])(C([H])([H])[H])C([H])([H])[H])=O)C1C([H])=C([H])C(C([H])([H])O[H])=C([H])C=1[C@@]([H])(C1C([H])=C([H])C([H])=C([H])C=1[H])C([H])([H])C([H])([H])N(C([H])(C([H])([H])[H])C([H])([H])[H])C([H])(C([H])([H])[H])C([H])([H])[H]

DCCSDBARQIPTGU-HSZRJFAPSA-N

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

[2-[(1R)-3-[di(propan-2-yl)amino]-1-phenylpropyl]-4-(hydroxymethyl)phenyl] 2-methylpropanoate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: (1). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.  (2). This product is not stable in solution, please use freshly prepared working solution for optimal results.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~242.97 mM)
Ethanol : ~50 mg/mL (~121.48 mM)

Solubility in Formulation 1: ≥ 2.75 mg/mL (6.68 mM) (saturation unknown) in 10% EtOH + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear EtOH stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.75 mg/mL (6.68 mM) (saturation unknown) in 10% EtOH + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear EtOH stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.75 mg/mL (6.68 mM) (saturation unknown) in 10% EtOH + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear EtOH stock solution to 900 μL of corn oil and mix well.

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Solubility in Formulation 4: ≥ 2.5 mg/mL (6.07 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 5: ≥ 2.5 mg/mL (6.07 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)