M₁ receptor ( Kd = 2.9 nM ); M₂ receptor ( Kd = 6.9 ); M₃ receptor ( Kd = 8.0 )

体外活性：Solifenacin（以前称为 YM905）是一种新型、有效的毒蕈碱受体拮抗剂，对于 M1、M2 和 M3 受体的 pK 分别为 7.6、6.9 和 8.0。静脉注射 0.03 mg/kg 或更高剂量的索利那新可增加膀胱容量和排尿量。托特罗定静脉注射0.03和0.1 mg/kg可增加膀胱容量和排尿量，而静脉注射1 mg/kg和0.3和1 mg/kg的丙哌维林分别增加膀胱容量和排尿量。相比之下，三种药物均不影响残余尿量或排尿压力。这些结果表明，索利那新可以改善逼尿肌过度活动而不引起尿潴留，并且可能是治疗膀胱过度活动综合征患者的有前途的药物。激酶测定：Solifenacin 是一种新型毒蕈碱受体拮抗剂，对于 M1、M2 和 M3 受体的 pK 分别为 7.6±0.056、6.9±0.034 和 8.0±0.021。细胞测定：在小鼠颌下腺细胞中，检查了 100 nM Solifenacin 和奥昔布宁对不同剂量的卡巴胆碱 (CCh) 引起的 Ca2+ 动员的拮抗作用。索利那新不会以平行方式改变 CCh 剂量激活曲线，而奥昔布宁则显示出难以克服的拮抗作用。索利那新的 pKb 值为 7.4±0.17，奥昔布宁的 pKb 值为 8.8±0.21。在豚鼠逼尿肌细胞中测定胞质 Ca2+ 动员。简而言之，从无上皮的膀胱中制备单个逼尿肌细胞，负载 Fura 2，并悬浮在补充有 20 mM HEPES (pH=7.4) 和 0.1% 牛血清白蛋白 (HBSS-H) 的无酚红 Hanks 平衡盐溶液中。 /B）。连续搅拌 490 μL 等份细胞悬浮液，保持在 28°C，并监测 340 nm 激发下 500 nm 荧光与 380 nm 激发荧光的比率。向每个等分试样中，以2分钟的间隔连续添加5μL测试药物（包括索非那新）和刺激剂溶液，并且将刺激前水平的峰值增加用于数据分析。

索利那新在剂量为 210 nmol/kg (0.1 mg/kg) 时使膀胱反应降低 40%，在剂量为 2100 nmol/kg (1 mg/kg) 时消除膀胱反应。相比之下，其对唾液和心脏反应的抑制作用在630 nmol/kg（0.3 mg/kg）时仅轻微，在2100 nmol/kg（1 mg/kg）时分别达到66%和49%。剂量为 63 和 210 nmol/kg（0.03 和 0.1 mg/kg）时，索利那新会轻微增加唾液分泌。索利那新（0.01至0.3 mg/kg iv）剂量依赖性地增加膀胱容量和排尿量，剂量为0.03 mg/kg iv或更高，但在任何测试剂量下不影响残余容量或排尿压力

在豚鼠逼尿肌细胞中，测量胞质 Ca²⁺ 的动员。总之，使用添加了 20 mM HEPES (pH=7.4) 和 0.1% 牛血清白蛋白 (HBSS-H/B) 的无酚红 Hanks 平衡盐溶液从无上皮膀胱中制备单个逼尿肌细胞，将其加载与 Fura 2 一起，并将它们悬浮在溶液中。取490 μL细胞悬液不断混合，维持在28°C，观察340 nm激发时500 nm与380 nm荧光的比率。将五微升测试药物（例如索利那新）和兴奋剂溶液以两分钟的间隔连续添加到每个等分试样中。刺激前水平的峰值增加用于数据分析[1]。

Absorption, Distribution and Excretion
Solifenacin is well absorbed in the duodenum, jejunum, and ileum but not the stomach. Absorption occurs via passive diffusion and so no transporters are involved. The mean oral bioavailability of solifenacin is 88%. The Tmax of solifenacin is 3-8 hours with a Css of 32.3ng/mL for a 5mg oral dose and 62.9ng/mL for a 10mg oral dose.
69.2±7.8% of a radiolabelled dose is recovered in the urine, 22.5±3.3% was recovered in feces, and 0.4±7.8% was recovered in exhaled air. 18% of solifenacin is eliminated as the N-oxide metabolite, 9% is eliminated as the 4R-hydroxy N-oxide metabolite, and 8% is eliminated as the 4R-hydroxy metabolite.
The volume of distribution of solifenacin is 600L.
The clearance of solifenacin is 7-14L/h and a renal clearance of 0.67-1.51L/h.

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Metabolism / Metabolites
Solifenacin undergoes N-oxidation at the quinuclidin ring by cytochrome P450, though the exact enzymes are not revealed in the literature. The tetrahydroisoquinolone ring is 4R-hydroxylated by CYP3A4, CYP1A1, and CYP2D6. A 4R-hydroxy N-oxide metabolite is also formed by CYP3A4. Finally, solifenacin can undergo direct glucuronidation. Only solifenacin and the 4R-hydroxy metabolite are pharmacologically active.

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Biological Half-Life
The elimination half life of solifenacin ranges from 33-85 hours.

Hepatotoxicity
Like most anticholinergic agents, solifenacin has not been linked to liver enzyme elevations during therapy or to instances of clinically apparent liver injury with jaundice. In multiple prospective clinical trials of solifenacin in patients with overactive bladder syndrome, ALT elevations were reported in less than 1% of treated subjects, rates similar to that of placebo-recipients. Despite widespread clinical use for almost two decades, there has been only a single published case report of possible liver injury due to darifenacin use. An elderly woman with end stage liver injury developed transient elevations of serum aminotransferases and alkaline phosphatase without jaundice two weeks after starting solifenacin. Thus, liver injury due to solifenacin must be rare if it occurs at all.
Likelihood score: D (possible, very rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because there is no published experience with solifenacin during breastfeeding and it has a long half-life averaging 55 hours, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. Long-term use of solifenacin might reduce milk production or milk letdown. During long-term use, observe the infant for signs of decreased milk production (e.g., insatiety, poor weight gain) and for anticholinergic symptoms (e.g., constipation, urinary retention, UTI, dry mouth).
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Anticholinergics can inhibit lactation in animals, apparently by inhibiting growth hormone and oxytocin secretion. Anticholinergic drugs can also reduce serum prolactin in nonnursing women. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

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Protein Binding
Solifenacin is 93-96% protein bound in plasma, mainly to alpha-1-acid glycoprotein.

[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 is a member of isoquinolines.
Solifenacin is a competitive muscarinic receptor antagonist indicated to treat an overactive bladder with urinary incontinence, urgency, and frequency. It has a long duration of action as it is usually taken once daily. Solifenacin was granted FDA approval on 19 November 2004.
Solifenacin is a Cholinergic Muscarinic Antagonist. The mechanism of action of solifenacin is as a Cholinergic Muscarinic Antagonist.
Solifenacin is an anticholinergic and antispasmodic agent used to treat urinary incontinence and the overactive bladder syndrome. Solifenacin has not been implicated in causing liver enzyme elevations or clinically apparent acute liver injury.
A quinuclidine and tetrahydroisoquinoline derivative and selective M3 MUSCARINIC ANTAGONIST. It is used as a UROLOGIC AGENT in the treatment of URINARY INCONTINENCE.
See also: Solifenacin Succinate (has salt form).

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Drug Indication
Solifenacin tablets are indicated to treat an 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, while 20% are M3. Solifenacin's antagonism of the M3 receptor prevents contraction of the detrusor muscle, while antagonism of the M2 receptor may prevent contraction of smooth muscle in the bladder.

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Pharmacodynamics
Solifenacin antagonizes the M2 and M3 muscarinic receptors in the bladder to treat an overactive bladder. It has a long duration of action as it is usually taken once daily. Patients taking solifenacin should be aware of the risks of angioedema and anaphylaxis.

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

32.78

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (6.90 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (6.90 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (6.90 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。