The primary target of Tolterodine is muscarinic acetylcholine receptors, specifically M2 and M3 subtypes. It acts as a competitive antagonist, blocking the action of acetylcholine at these receptors. This antagonism results in inhibition of bladder contraction, decrease in detrusor pressure, and an incomplete emptying of the bladder.

In vitro, Tolterodine effectively inhibits muscarinic receptor activity with an IC50 of 14 nM. Its active metabolite, 5-HM, has an IC50 of 5.7 nM. The compound's selectivity for the urinary bladder over salivary glands has been confirmed in various in vitro models.

In vivo, Tolterodine is used to treat overactive bladder symptoms such as urinary frequency, urgency, and incontinence. It belongs to the class of drugs known as antimuscarinics, which work by blocking the action of acetylcholine, a neurotransmitter that stimulates the bladder muscles.

In vitro enzyme or receptor binding assays for Tolterodine involve studying its binding affinity for muscarinic receptors. Radioligand binding assays are performed using membrane preparations from cells expressing M2 and M3 receptors. The compound is incubated with a radiolabeled ligand, and the displacement of the ligand is measured to determine the affinity.

In vitro cell-based assays for Tolterodine are performed using cells expressing muscarinic receptors. Cells are treated with the compound, and the inhibition of acetylcholine-induced calcium mobilization or other signaling events is measured. The compound's potency and selectivity are assessed.

In vivo animal experiments for Tolterodine are conducted using rodent models of overactive bladder. The compound is administered orally, and its effects on bladder function, such as contraction frequency and volume, are assessed. These studies confirm the compound's efficacy as an antimuscarinic agent.

Absorption, Distribution and Excretion
Following oral administration of 5 mg 14C-tolterodine solution to healthy volunteers, 77% of the radioactive material was recovered in urine and 17% in feces within 7 days.
113 ± 26.7 L
Metabolism/Metabolites Known metabolites of tolterodine include 5-hydroxymethyltolterodine and N-desalkyltolterodine.
Biological Half-Life 1.9–3.7 hours
Pharmacokinetic (PK) properties of Tolterodine indicate that it has a molecular weight of 325.49 and a molecular formula of C22H31NO. The CAS number is 124937-51-5. The IUPAC name is 2-[(1R)-3-[Bis(1-methylethyl)amino]-1-phenylpropyl]-4-methylphenol. It is soluble in methanol and slightly soluble in ethanol. It has a pKa of 9.87.

Hepatotoxicity
In multiple randomized controlled trials of tolterodine for patients with overactive bladder, elevated serum transaminases and alkaline phosphatase levels were uncommon, with an incidence of less than 1% in both the treatment and placebo groups. No clinically significant liver injury or jaundice was reported in these clinical trials. Since tolterodine was approved and widely used in 1998 (with over 1 million prescriptions annually in the US), only one published case report has shown liver injury symptoms and jaundice after tolterodine use (Case 1). Therefore, acute symptomatic liver injury caused by tolterodine, even if it occurs, is certainly very rare. Probability Score: D (Possibly, but extremely rare, a cause of clinically significant liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation There is currently no information on the use of tolterodine during lactation. Long-term use of tolterodine may reduce milk production or the milk ejection reflex. During long-term use, signs of decreased lactation (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
Anticholinergic drugs can inhibit lactation in animals, possibly by suppressing 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
Approximately 96.3%.
Toxicology (toxicology) data for Tolterodine indicate that it is generally well-tolerated. Common side effects include dry mouth, constipation, and blurred vision, which are typical of antimuscarinic agents. The compound should be used with caution in patients with glaucoma or urinary retention.

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

[2]. Biotransformation of tolterodine, a new muscarinic receptor antagonist, in mice, rats, and dogs. Drug Metab Dispos. 1998 Jun;26(6):528-35.

[3]. Tolterodine does not affect memory assessed by passive-avoidance response test in mice. Eur J Pharmacol. 2008 Jan 28;579(1-3):225-8.

Tolterodine is a tertiary amine. It acts as a muscarinic receptor antagonist, muscle relaxant, and antispasmodic. Its function is similar to that of p-cresol. Tolterodine is an antimuscarinic drug used to treat urinary incontinence. Tolterodine acts on the M2 and M3 subtypes of muscarinic receptors. Tolterodine is a cholinergic muscarinic receptor antagonist. The mechanism of action of tolterodine is as a cholinergic muscarinic receptor antagonist. Tolterodine is an anticholinergic drug used to treat urinary incontinence and overactive bladder. No association has been found between tolterodine treatment and elevated liver enzymes; only one case of clinically significant acute liver injury has been reported, attributed to tolterodine use. Tolterodine tartrate is the tartrate salt form of tolterodine, a diphenylmethyl compound that is also a muscarinic receptor antagonist with antimuscarinic and antispasmodic effects. Tolterodine and its active metabolite, 5-hydroxymethyltolterodine, both competitively block muscarinic receptors, thereby inhibiting the binding of acetylcholine receptors. This antagonistic effect leads to increased residual urine volume, reflecting incomplete bladder emptying, and reduces detrusor pressure, indicating an antimuscarinic effect on the lower urinary tract. The 5-hydroxymethyl metabolite appears to contribute significantly to the therapeutic effect. Tolterodine is a diphenylmethyl compound and a muscarinic receptor antagonist with antimuscarinic and antispasmodic effects. Tolterodine and its active metabolite, 5-hydroxymethyltolterodine, both competitively block muscarinic receptors, thereby inhibiting the binding of acetylcholine. This antagonistic effect leads to increased residual urine volume, reflecting incomplete bladder emptying, and reduces detrusor pressure, indicating an antimuscarinic effect on the lower urinary tract. The 5-hydroxymethyl metabolite appears to contribute significantly to the therapeutic effect.
An antimuscarinic drug that selectively acts on bladder muscarinic receptors for the treatment of urinary incontinence and urge incontinence.
See also: Tolterodine tartrate (in saline form).
Drug Indications

For the treatment of overactive bladder (with symptoms of urinary frequency, urgency, or urge incontinence).
FDA Label
Mechanism of Action

Tolterodine and its active metabolite 5-hydroxymethyltolterodine both act as competitive antagonists of muscarinic receptors. This antagonism results in inhibition of bladder contraction, decreased detrusor pressure, and incomplete bladder emptying.
Pharmacodynamics

Tolterodine is a competitive muscarinic receptor antagonist. Bladder contraction and salivation are mediated by cholinergic muscarinic receptors. After oral administration, tolterodine is metabolized in the liver to produce a 5-hydroxymethyl derivative, which is the primary pharmacologically active metabolite. The 5-hydroxymethyl metabolite possesses antimuscarinic activity similar to tolterodine and significantly contributes to therapeutic efficacy. Both tolterodine and its 5-hydroxymethyl metabolite exhibit high specificity for muscarinic receptors, as their activity or affinity for other neurotransmitter receptors and other potential cellular targets (such as calcium channels) is negligible. Tolterodine has a significant effect on bladder function. Its primary action is to increase residual urine volume, reflecting incomplete bladder emptying, and to decrease detrusor pressure, consistent with its anticholinergic effects on the lower urinary tract.
Other information: Tolterodine is also known as PNU-200583. It is a potent muscarinic receptor antagonist used for the treatment of overactive bladder. The compound is marketed under the brand name Detrol. Its CAS number is 124937-51-5.

C22H31NO

325.48764

325.24

C, 81.18; H, 9.60; N, 4.30; O, 4.92

124937-51-5

Tolterodine tartrate; 124937-52-6; Tolterodine-d14 hydrochloride; 1217645-16-3

443879

Colorless to light yellow solid powder

1.0±0.1 g/cm3

442.2±45.0 °C at 760 mmHg

192.1±27.4 °C

0.0±1.1 mmHg at 25°C

1.548

5.77

1

2

7

24

340

1

CC(C)N(C(C)C)CC[C@H](C1=CC=CC=C1)C2=C(O)C=CC(C)=C2

OOGJQPCLVADCPB-HXUWFJFHSA-N

InChI=1S/C22H31NO/c1-16(2)23(17(3)4)14-13-20(19-9-7-6-8-10-19)21-15-18(5)11-12-22(21)24/h6-12,15-17,20,24H,13-14H2,1-5H3/t20-/m1/s1

2-[(1R)-3-[di(propan-2-yl)amino]-1-phenylpropyl]-4-methylphenol

Detrusitol; Tolterodine; Detrol; PHA-686464B

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

Ethanol: ~120 mg/mL (~368.7 mM)
DMSO: ~100 mg/mL (~307.2 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (6.39 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 20.8 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 2: ≥ 2.08 mg/mL (6.39 mM) (saturation unknown) in 10% DMSO + 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 20.8 mg/mL clear DMSO 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: ≥ 2.08 mg/mL (6.39 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 20.8 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.)