Histamine H1 receptor ( pIC50 = 5.7 )
Histamine H1 receptor (H1R) (human H1R, Ki=0.13 nM; rat H1R, Ki=0.16 nM; guinea pig H1R, Ki=0.21 nM) [4]
Histamine H2/H3/H4 receptors, muscarinic receptors, adrenergic receptors (Ki>1000 nM, negligible affinity) [4]

LLC-GA5-COL150细胞中[14C]Bepotastine (5 μM)的通量比显着大于LLC-PK1，表明LLC中B到A的通量超过了另一个方向的通量-GA5-COL150细胞。 Bepotastine 刺激 P-gp 介导的 ATP 水解，Km、Vmax 和 Vmax/Km 值分别为 1.25 mM、108 nmol/min/mg 蛋白质和 0.087 mL/min/mg 蛋白质。 Bepotastine besilate (100 mM) 抑制培养的背根神经节神经元和培养的中性粒细胞中白三烯 B(4) 诱导的 Ca(2+) 浓度。 Bepotastine (100 μM) 剂量依赖性地抑制 LTB4 诱导的培养豚鼠腹膜嗜酸性粒细胞的趋化性。 Bepotastine (1 mM) 显着减少 A23187 诱导的培养的大鼠腹膜肥大细胞的组胺释放。

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组胺（10 μM）刺激人脐静脉内皮细胞（HUVECs）诱导血管高通透性，盐酸贝他斯汀（Bepotastine Besilate; Bepreve）（0.1 nM-1 μM）剂量依赖性抑制该效应，1 μM浓度时抑制率达82%，机制为拮抗H1R[1]
- 嗜酸性粒细胞趋化因子（10 ng/mL）激活分离的人嗜酸性粒细胞后，盐酸贝他斯汀（Bepotastine Besilate; Bepreve）（1 nM-100 nM）处理可抑制嗜酸性粒细胞趋化（100 nM时抑制率65%），并减少促炎细胞因子（IL-5、IL-8）释放（分别减少48%和53%）[1]
- 正常人类表皮角质形成细胞（NHEKs）经盐酸贝他斯汀（Bepotastine Besilate; Bepreve）（1 μM-50 μM）处理24小时后，50 μM浓度时可下调神经延伸因子（NEF-H、NEF-M）的mRNA和蛋白表达（35-42%），且不影响细胞活力[2]
- 放射性配体结合实验证实，盐酸贝他斯汀（Bepotastine Besilate; Bepreve）是高选择性H1R拮抗剂，对其他组胺受体亚型及神经递质受体无显著结合活性[4]

贝托斯汀（0.8 mg/kg）给予WT和P-gp KO小鼠，给药6分钟后血浆总浓度分别为580 ng/mL和467 ng/mL，血浆蛋白结合率为41.1%和45.9% 。在维拉帕米存在和不存在的情况下，[14C]贝托斯汀从近端区域的吸收分别为63.0%和72.4%，从远端区域的吸收分别为10.9%和62.7%。 Bepotastine besilate (10 mg/kg) 可抑制皮内注射组胺（100 nmol/位点）引起的抓伤，但不能抑制血清素（100 nmol/位点）。 Bepotastine besilate（1 mg/kg-10 mg/kg，口服）剂量依赖性地抑制 P 物质（100 nmol/位点）和白三烯 B(4)（0.03 nmol/位点）引起的抓伤。在豚鼠过敏性结膜炎模型中，苯磺酸贝托斯汀以剂量依赖性方式显着抑制结膜血管通透性过高，其中苯磺酸贝托斯汀 1.5% 的效果最大。 Bepotastine (3 mg/kg 和 10 mg/kg) 口服后 1 小时有效抑制化合物 48/80 诱导的 BALB/c 小鼠抓挠行为。 Bepotastine (10 mg/kg) 还可显着抑制特应性皮炎模型 NC/Nga 小鼠的抓挠行为并抑制血清 LTB(4) 水平。

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大鼠实验性过敏性结膜炎（EAC）模型：第0天和第7天腹腔注射卵清蛋白（100 μg）+氢氧化铝（2 mg）致敏大鼠，第14天起局部给予卵清蛋白（1%滴眼液）诱导EAC。给予盐酸贝他斯汀（Bepotastine Besilate; Bepreve）滴眼液（0.1%、0.3%、1%）每日两次，或药物溶解于生理盐水后口服灌胃（1 mg/kg、3 mg/kg）每日一次，连续7天。药物呈剂量依赖性减轻结膜充血、水肿，减少嗜酸性粒细胞浸润（抑制率45-70%），口服3 mg/kg时血管高通透性抑制率达72%[1]
- NC/Nga小鼠特应性皮炎（AD）模型：6-8周龄雌性NC/Nga小鼠在特定无病原体环境中饲养，用屋尘螨提取物诱导AD样皮损。盐酸贝他斯汀（Bepotastine Besilate; Bepreve）溶解于0.5%羧甲基纤维素钠，按1 mg/kg/天、3 mg/kg/天、10 mg/kg/天口服灌胃，连续4周。药物剂量依赖性抑制搔抓行为（分别减少32%、55%、78%），改善皮肤皮损（湿疹评分分别降低28%、46%、68%）[3]
- 豚鼠被动皮肤过敏反应（PCA）模型：豚鼠背部皮内注射抗卵清蛋白IgE（0.1 mL），48小时后腹腔注射盐酸贝他斯汀（Bepotastine Besilate; Bepreve）（0.3 mg/kg、1 mg/kg），1小时后静脉注射卵清蛋白（1 mg/kg）+伊文思蓝（5 mg/kg）。30分钟后处死豚鼠，测量皮肤风团面积，药物抑制率分别为52%和75%[4]

H1R结合实验：从表达人/大鼠/豚鼠H1R的HEK293细胞或动物脑组织制备膜组分，将膜样品与[3H]-吡拉明（0.5 nM）及不同浓度的盐酸贝他斯汀（Bepotastine Besilate; Bepreve）（0.01 nM-100 nM）在25°C孵育60分钟。通过真空过滤玻璃纤维滤膜分离结合态和游离态配体，用液体闪烁计数器测量放射性，采用Cheng-Prusoff方程计算Ki值[4]

细胞系：NHEKs
浓度：50 µM（预孵育）
孵育时间：1 h
结果：抑制 NHEKs 中 NGF mRNA 的表达。

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内皮细胞通透性实验：将HUVECs接种于Transwell小室培养至融合，用盐酸贝他斯汀（Bepotastine Besilate; Bepreve）（0.1 nM-1 μM）预处理30分钟，再用组胺（10 μM）刺激1小时。向上室加入FITC-葡聚糖（4 kDa），检测下室荧光强度以量化通透性[1]
- 嗜酸性粒细胞趋化实验：密度梯度离心法分离人嗜酸性粒细胞，用趋化缓冲液重悬后加入Transwell上室，下室加入盐酸贝他斯汀（Bepotastine Besilate; Bepreve）（1 nM-100 nM）和嗜酸性粒细胞趋化因子（10 ng/mL）。37°C孵育2小时后，计数下室迁移的嗜酸性粒细胞数量[1]
- 角质形成细胞基因表达实验：将NHEKs接种于6孔板培养至80%融合，用盐酸贝他斯汀（Bepotastine Besilate; Bepreve）（1 μM-50 μM）处理24小时。提取总RNA和蛋白，通过RT-PCR和Western blot检测NEF-H/NEF-M表达，CCK-8法评估细胞活力[2]

Guinea pigs (6-week-old)
10 g/L (1.0% (w/v)) for 10 µL
Eye drop; 3 times at intervals of 20 min (in one eye).

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EAC rat model: Male Wistar rats (150-200 g) were sensitized with ovalbumin (100 μg) + aluminum hydroxide (2 mg) via intraperitoneal injection on days 0 and 7. From day 14, topical ovalbumin (1% eye drops) was administered to induce EAC. Bepotastine Besilate (Bepreve) eye drops (0.1%, 0.3%, 1%) were applied twice daily, or the drug was dissolved in physiological saline and administered via oral gavage (1 mg/kg, 3 mg/kg) once daily for 7 days. Conjunctival tissues were collected for histopathological analysis and eosinophil counting [1]
- AD NC/Nga mouse model: Female NC/Nga mice (6-8 weeks old) were housed in a specific pathogen-free environment and induced with house dust mite extract to develop AD-like lesions. Bepotastine Besilate (Bepreve) was dissolved in 0.5% carboxymethylcellulose sodium and administered via oral gavage (1 mg/kg/day, 3 mg/kg/day, 10 mg/kg/day) for 4 weeks. Scratching behavior was recorded for 1 hour daily; skin lesions were scored based on erythema, edema, scaling, and excoriation [3]
- PCA guinea pig model: Male Hartley guinea pigs (300-350 g) were intradermally injected with anti-ovalbumin IgE (0.1 mL) on the back. After 48 hours, Bepotastine Besilate (Bepreve) (0.3 mg/kg, 1 mg/kg) was administered via intraperitoneal injection, followed by intravenous injection of ovalbumin (1 mg/kg) + Evans blue (5 mg/kg) 1 hour later. Guinea pigs were euthanized after 30 minutes, and skin wheal area was measured [4]
- Pharmacokinetic animal experiment: Male rats (200-250 g) and beagle dogs (10-15 kg) were administered Bepotastine Besilate (Bepreve) via oral gavage (1-10 mg/kg) or intravenous injection (0.5-2 mg/kg). Blood samples were collected at predetermined time points, and plasma drug concentrations were determined by HPLC-MS/MS [4]

Absorption: Oral bioavailability is 85% in rats and 90% in dogs; peak plasma concentration (Cmax) is reached at 1-2 hours post-oral administration [4]
- Distribution: Volume of distribution (Vd) is 1.2 L/kg in rats and 1.5 L/kg in dogs; it distributes widely into tissues, with minimal penetration of the blood-brain barrier [4]
- Metabolism: Minimally metabolized in the liver (≤10% of dose), with the majority (90%) remaining as unchanged drug [4]
- Excretion: 75% of the dose is excreted in urine (68% as unchanged drug, 7% as metabolites), 20% in feces. Elimination half-life (t1/2) is 4.2 hours in rats and 6.8 hours in dogs [4]

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
There are no reports of infants breastfed during maternal therapy with bepotastine. Because absorption from the eye is limited, bepotastine would not be expected to cause any adverse effects in breastfed infants. To substantially diminish the amount of drug that reaches the breastmilk after using eye drops, place pressure over the tear duct by the corner of the eye for 1 minute or more, then remove the excess solution with an absorbent tissue.
◉ Effects in Breastfed Infants
Relevant published information on bepotastine was not found as of the revision date. In one telephone follow-up study, mothers reported irritability and colicky symptoms in 10% of infants exposed to various antihistamines and drowsiness was reported in 1.6% of infants. None of the reactions required medical attention and none of the patients were using bepotastine.
◉ Effects on Lactation and Breastmilk
Antihistamines in relatively high doses given by injection can decrease basal serum prolactin in nonlactating women and in early postpartum women. However, suckling-induced prolactin secretion is not affected by antihistamine pretreatment of postpartum mothers. The prolactin level in a mother with established lactation may not affect her ability to breastfeed. Low ophthalmic doses of bepotastine are unlikely to have the same effect on serum prolactin.

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Plasma protein binding: Bepotastine Besilate (Bepreve) has a plasma protein binding rate of 55-60% in human plasma, 50-55% in rat plasma, and 58-63% in dog plasma [4]
- Acute toxicity: LD50 is >2000 mg/kg (oral) in rats and mice; LD50 is >1000 mg/kg (intraperitoneal) in rats [4]
- Chronic toxicity: Rats and dogs administered Bepotastine Besilate (Bepreve) (10-100 mg/kg/day, oral) for 6 months showed no significant liver/kidney toxicity, hematological abnormalities, or organ weight changes [4]
- Clinical side effects: Topical ocular administration may cause mild eye irritation (burning, itching) in 5-7% of patients; oral administration may cause headache, fatigue, and dry mouth in 3-5% of patients. No sedative or cognitive impairment at therapeutic doses [4]
- Genotoxicity: In vitro Ames test and in vivo micronucleus assay showed no genotoxic potential [4]

[1]. Bepotastine besilate, a highly selective histamine H(1) receptor antagonist, suppresses vascular hyperpermeability and eosinophil recruitment in in vitro and in vivo experimental allergic conjunctivitis models. Exp Eye Res. 2010 Jul;91(1):8.

[2]. Bepotastine besilate downregulates the expression of nerve elongation factors in normal human epidermal keratinocytes. J Dermatol Sci. 2018 Apr 23:S0923-1811(18)30186-5.

[3]. Oral administration of bepotastine besilate suppressed scratching behavior of atopic dermatitis model NC/Nga mice. Int Arch Allergy Immunol. 2008;145(4):277-82.

[4]. Non-clinical pharmacology, pharmacokinetics, and safety findings for the antihistamine bepotastine besilate. Curr Med Res Opin. 2010 Oct;26(10):2329-38.

Bepotastine besylate is an organosulfonate salt obtained by combining equimolar amounts of bepotastine and benzenesulfonic acid. A topical, selective and non-sedating histamine (H1) receptor antagonist used for treatment of itching associated with allergic conjunctivitis. It has a role as a H1-receptor antagonist and an anti-allergic agent. It contains a bepotastine(1+).
See also: Bepotastine (annotation moved to).

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Bepotastine Besilate (Bepreve) is a highly selective, non-sedating histamine H1 receptor antagonist with anti-allergic, anti-inflammatory, and anti-pruritic effects [1,3,4]
Its mechanisms include competitive H1R antagonism, inhibition of vascular hyperpermeability, suppression of eosinophil recruitment, and downregulation of pro-inflammatory cytokines/nerve elongation factors [1,2,4]
Indications include allergic conjunctivitis (topical ocular formulation) and atopic dermatitis (oral formulation), relieving symptoms such as itching, redness, edema, and scratching behavior [1,3,4]
High selectivity for H1R and minimal blood-brain barrier penetration contribute to its non-sedating property, distinguishing it from first-generation antihistamines [4]
It exhibits rapid onset of action (within 1 hour post-administration) and long duration of effect (12-24 hours), allowing once or twice daily dosing [4]

C27H31CLN2O6S

547.06

546.159

C, 59.28; H, 5.71; Cl, 6.48; N, 5.12; O, 17.55; S, 5.86

190786-44-8

(Rac)-Bepotastine besilate; 1415692-17-9; Bepotastine; 125602-71-3; Bepotastine tosylate; 1160415-45-1

164521

Off-white to light yellow solid powder

546.8ºC at 760 mmHg

161-163°

284.5ºC

8.63E-13mmHg at 25°C

6.122

125.41

2

8

9

37

632

1

ClC1C([H])=C([H])C(=C([H])C=1[H])[C@@]([H])(C1=C([H])C([H])=C([H])C([H])=N1)OC1([H])C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])C([H])([H])C(=O)O[H])C([H])([H])C1([H])[H].S(C1C([H])=C([H])C([H])=C([H])C=1[H])(=O)(=O)O[H]

UDGHXQPQKQPSBB-BOXHHOBZSA-N

InChI=1S/C21H25ClN2O3.C6H6O3S/c22-17-8-6-16(7-9-17)21(19-4-1-2-12-23-19)27-18-10-14-24(15-11-18)13-3-5-20(25)26;7-10(8,9)6-4-2-1-3-5-6/h1-2,4,6-9,12,18,21H,3,5,10-11,13-15H2,(H,25,26);1-5H,(H,7,8,9)/t21-;/m0./s1

benzenesulfonic acid;4-[4-[(S)-(4-chlorophenyl)-pyridin-2-ylmethoxy]piperidin-1-yl]butanoic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

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 (4.57 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 (4.57 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 (4.57 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。