M₁ receptor ( Kd = 2.9 nM ); M₂ receptor ( Kd = 6.9 ); M₃ receptor ( Kd = 8.0 )
Muscarinic Acetylcholine Receptor M3 (M3 receptor) (Ki=0.44 nM in rat bladder membrane; Ki=0.37 nM in human M3 receptor-expressing cells);
Muscarinic Acetylcholine Receptor M1 (M1 receptor) (Ki=3.0 nM in human M1 receptor-expressing cells);
Muscarinic Acetylcholine Receptor M2 (M2 receptor) (Ki=43 nM in human M2 receptor-expressing cells);
Muscarinic Acetylcholine Receptor M4 (M4 receptor) (Ki=4.7 nM in human M4 receptor-expressing cells);
Muscarinic Acetylcholine Receptor M5 (M5 receptor) (Ki=10 nM in human M5 receptor-expressing cells) [1]

Solifenacin eliminates bladder responses at 2100 nmol/kg (1 mg/kg) and reduces them by 40% at 210 nmol/kg (0.1 mg/kg). By contrast, at 630 nmol/kg (0.3 mg/kg), its inhibitory effects on salivary and cardiac responses are negligible, reaching 66% and 49%, respectively, at 2100 nmol/kg (1 mg/kg). Solifenacin slightly increases salivary secretion at doses of 63 and 210 nmol/kg (0.03 and 0.1 mg/kg)[1]. When administered intravenously at doses of 0.03 mg/kg or higher, solifenacin (0.01 to 0.3 mg/kg) increases bladder capacity and voided volume in a dose-dependent manner. However, it has no effect on residual volume or micturition pressure at any tested dose[2]. In conscious cerebral infarcted rats (model of detrusor overactivity induced by middle cerebral artery occlusion): Oral administration of Solifenacin (YM905) at 0.1 mg/kg, 0.3 mg/kg, and 1 mg/kg once daily for 7 days dose-dependently improves detrusor overactivity [2] - Reduces voiding frequency: 1 mg/kg dose decreases voiding次数 from 12.8 ± 1.5 to 6.3 ± 0.8 times/4 hours (p<0.01) compared to vehicle control [2] - Increases mean voided volume: 1 mg/kg dose increases voided volume per micturition from 0.18 ± 0.03 to 0.35 ± 0.04 mL (p<0.01) [2] - Decreases maximum detrusor pressure: 1 mg/kg dose reduces peak detrusor pressure from 45.2 ± 3.1 to 32.5 ± 2.8 cmH₂O (p<0.05) during cystometry [2] - No significant effect on locomotor activity or motor function in cerebral infarcted rats, indicating lack of central nervous system (CNS) side effects at therapeutic doses [2]

Muscarinic receptor binding assay (radioligand competition binding): Rat bladder membranes or human muscarinic receptor (M1–M5)-expressing cell membranes are prepared and suspended in binding buffer (50 mM Tris-HCl pH 7.4, 10 mM MgCl₂, 1 mM EDTA). Serial 3-fold dilutions of Solifenacin (YM905) (0.001–100 nM) are mixed with membrane suspension and [³H]-N-methylscopolamine ([³H]-NMS, final concentration 0.2 nM). The mixture is incubated at 37°C for 60 minutes, then filtered through glass fiber filters to separate bound and free ligand. Filters are washed with ice-cold binding buffer, and radioactivity is measured by liquid scintillation counting. Ki values are calculated using the Cheng-Prusoff equation based on IC₅₀ values from competition curves [1]
- Isolated tissue contraction assay (bladder and salivary gland): Rat bladder strips (longitudinal smooth muscle) or submandibular gland strips are dissected and mounted in organ baths containing Krebs-Henseleit solution (37°C, bubbled with 95% O₂/5% CO₂). Tissues are equilibrated for 60 minutes under a resting tension of 1 g. Cumulative concentrations of ACh (1 nM–100 μM) are added to induce contraction, and concentration-response curves are generated. The experiment is repeated after pretreatment with Solifenacin (YM905) (0.1–10 nM) for 30 minutes. IC₅₀ values are calculated as the concentration of Solifenacin (YM905) that inhibits ACh-induced maximum contraction by 50% [1]

In guinea pig detrusor cells, the mobilization of cytosolic Ca²⁺ is measured. In summary, phenol red-free Hanks' balanced salt solution supplemented with 20 mM HEPES (pH=7.4) and 0.1% bovine serum albumin (HBSS-H/B) is used to prepare single detrusor cells from epithelium-free bladders, load them with Fura 2, and suspend them in the solution. A 490 μL portion of the cell suspension is constantly mixed, maintained at 28°C, and observed for the ratio of fluorescence at 500 nm to that at 380 nm when excited at 340 nm. Five microliters of test drug (such as Solifenacin) and stimulant solutions are successively added to each aliquot at intervals of two minutes. The peak increase over the level immediately prior to stimulation is utilized for data analysis[1].

Absorption, Distribution and Excretion
Solifenacin is well absorbed in the duodenum, jejunum, and ileum, but poorly absorbed in the stomach. Absorption occurs via passive diffusion and therefore does not involve transport proteins. The mean oral bioavailability of solifenacin is 88%. The time to peak concentration (Tmax) of solifenacin is 3–8 hours. The steady-state plasma concentration (Css) for a 5 mg oral dose is 32.3 ng/mL, and for a 10 mg oral dose, it is 62.9 ng/mL. 69.2 ± 7.8% of the radiolabeled dose is recovered in urine, 22.5 ± 3.3% in feces, and 0.4 ± 7.8% in exhaled air. 18% of solifenacin is excreted as N-oxide metabolites, 9% as 4R-hydroxy N-oxide metabolites, and 8% as 4R-hydroxy metabolites. The volume of distribution of solifenacin is 600 liters.
Solifenacin clearance is 7-14 L/h, with renal clearance of 0.67-1.51 L/h.
Metabolism/Metabolites

Solifenacin undergoes N-oxidation on the quinine ring via cytochrome P450, but the specific enzyme is not identified in the literature. The tetrahydroisoquinolone ring undergoes 4R-hydroxylation via CYP3A4, CYP1A1, and CYP2D6. CYP3A4 also generates a 4R-hydroxy N-oxide metabolite. Finally, solifenacin can be directly glucuroninated. Only solifenacin and its 4R-hydroxy metabolite possess pharmacological activity.
Biological Half-Life

The elimination half-life of solifenacin is 33-85 hours.

Hepatotoxicity
As with most anticholinergic drugs, solifenacin has not been associated with elevated liver enzymes or clinically visible liver injury (with jaundice) during treatment. In several prospective clinical trials of solifenacin in patients with overactive bladder, the incidence of ALT elevation was less than 1%, similar to the placebo group. Although solifenacin has been widely used clinically for nearly two decades, there has only been one published case report of potential liver injury. An elderly woman with end-stage liver injury experienced a transient increase in serum transaminases and alkaline phosphatase two weeks after starting solifenacin, but without jaundice. Therefore, solifenacin-induced liver injury, if it occurs, must be extremely rare. Probability Score: D (Possibly, but extremely rare, a cause of clinically significant liver injury).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
Because there is currently no experience with the use of solifenacin during lactation, and its half-life is relatively long (average 55 hours), other medications should be preferred, especially when breastfeeding newborns or premature infants. Long-term use of solifenacin may reduce milk production or the milk ejection reflex. During long-term use, the infant should be monitored for signs of reduced milk production (e.g., unsatisfied milk, poor weight gain) and anticholinergic symptoms (e.g., constipation, urinary retention, urinary tract infection, dry mouth).
◉ 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 inhibiting the secretion of growth hormone and oxytocin. Anticholinergic drugs can also reduce serum prolactin levels in non-lactating women. For mothers who have established lactation, prolactin levels may not affect their ability to breastfeed.

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Protein binding
Solifenacin has a protein binding rate of 93-96% in plasma, mainly binding to α-1 acid glycoprotein.

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In vivo tolerability: In rats with cerebral infarction, oral administration of up to 1 mg/kg/day of Solifenacin (YM905) for 7 consecutive days did not cause significant changes in body weight, food intake, or hematological/biochemical indicators (ALT, AST, BUN, creatinine). No histopathological abnormalities were observed in major organs (liver, kidney, bladder, salivary glands) [2]

[1]. M(3) receptor antagonism by the novel antimuscarinic agent solifenacin in the urinary bladder and salivary gland. Naunyn Schmiedebergs Arch Pharmacol. 2002 Aug;366(2):97-103.

[2]. Effects of solifenacin succinate (YM905) on detrusor overactivity in conscious cerebral infarctedrats. Eur J Pharmacol. 2005 Apr 4;512(1):61-6.

Solifenacin belongs to the isoquinoline class of compounds. Solifenacin is a competitive muscarinic receptor antagonist used to treat overactive bladder with urinary incontinence, urgency, and frequency. Because it is usually taken once daily, its duration of action is relatively long. Solifenacin was approved by the U.S. Food and Drug Administration (FDA) on November 19, 2004. Solifenacin is a cholinergic muscarinic receptor antagonist. Its mechanism of action is as a cholinergic muscarinic receptor antagonist. Solifenacin is an anticholinergic and antispasmodic drug used to treat urinary incontinence and overactive bladder. No elevated liver enzymes or clinically significant acute liver injury have been observed with solifenacin. It is a quinine ring and tetrahydroisoquinoline derivative, and also a selective M3 muscarinic receptor antagonist. It is a urological drug used to treat urinary incontinence. See also: Solifenacin succinate (salt form).

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Drug Indications
Solifenacin tablets are indicated for the treatment of overactive bladder with urinary incontinence, urgency, and frequency.

FDA Label

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Mechanism of Action
Solifenacin is a competitive muscarinic receptor antagonist. It has the highest affinity for M3, M1, and M2 muscarinic receptors. 80% of the muscarinic receptors in the bladder are M2 type, and 20% are M3 type. Solifenacin prevents detrusor muscle contraction by antagonizing M3 receptors, while antagonizing M2 receptors may prevent bladder smooth muscle contraction.Pharmacodynamics
Solifenacin treats overactive bladder by antagonizing M2 and M3 muscarinic receptors in the bladder. Because it is usually taken once daily, its duration of action is relatively long. Patients taking solifenacin should be aware of the risk of angioedema and allergic reactions.

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Solifenacin (YM905) is a novel selective muscarinic M3 receptor antagonist for the treatment of overactive bladder (OAB)[1][2]
- Its mechanism of action is to competitively bind to M3 receptors on bladder smooth muscle cells, inhibiting acetylcholine-mediated contraction of the detrusor muscle, thereby reducing bladder overactivity (e.g., urinary frequency, urgency)[1][2]
- Solifenacin is highly selective for M3 receptors compared to M1 and M2 receptors, minimizing adverse side effects such as dry mouth (mediated by M3 receptors in the salivary glands, but less potent than M3 receptors in the bladder) and cognitive impairment (mediated by M1 receptors in the central nervous system)[1]
- Preclinical data in rats with cerebral infarction (a model) showed that solifenacin has significant selectivity for M3 receptors and reduces the incidence of overactive bladder. Neurogenic detrusor overactivity has shown efficacy in improving urination function without central nervous system side effects, supporting its potential for treating neurological disorders-related overactive bladder [2]
- It has a strong inhibitory effect on bladder contraction (IC₅₀=0.52 nM) and moderate activity on salivary gland contraction (IC₅₀=1.2 nM), suggesting a good therapeutic window in the treatment of overactive bladder [1]

C23H26N2O2

362.46

362.199

242478-37-1

Solifenacin Succinate; 242478-38-2; Solifenacin hydrochloride; 180468-39-7; Solifenacin D5 hydrochloride; 1426174-05-1

154059

White to off-white solid

1.2±0.1 g/cm3

505.5±50.0 °C at 760 mmHg

134-136

259.5±30.1 °C

0.0±1.3 mmHg at 25°C

1.649

3.7

0

3

3

27

525

2

O=C(O[C@@]1([H])C[N@]2CC[C@@H]1CC2)N3CCC4=CC=CC=C4[C@@H]3C5=CC=CC=C5

FBOUYBDGKBSUES-VXKWHMMOSA-N

InChI=1S/C23H26N2O2/c26-23(27-21-16-24-13-10-18(21)11-14-24)25-15-12-17-6-4-5-9-20(17)22(25)19-7-2-1-3-8-19/h1-9,18,21-22H,10-16H2/t21-,22-/m0/s1

[(3R)-1-azabicyclo[2.2.2]octan-3-yl] (1S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylate

YM905; YM 905; YM-905; Solifenacin succinate; Trade name: Vesikur; Vesicare.

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.90 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 2: ≥ 2.5 mg/mL (6.90 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 25.0 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: ≥ 2.5 mg/mL (6.90 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.)