5-HT₃ Receptor ( IC50 = 17 μM )

体外活性：格拉司琼阻断猫离体心室肌细胞的延迟整流电流 (IK)，KD 为 4.3 mM。格拉司琼显示出固有的电压依赖性，因为阻滞随着去极化而增加。格拉司琼从细胞内侧的跨膜电场 10% 处的结合位点进行阻断。 Granisetron (3 mM) 可将猫离体心室肌细胞在 0.5 Hz 时的动作电位持续时间 (APD) 延长约 30%。格拉司琼（而非昂丹司琼）可以阻止假定的 5-H 的激活；自身受体，从而导致肠嗜铬细胞释放的血清素减少。细胞测定：在大鼠前胃中，GR 减少 5-HT 诱发的收缩，IC50 为 17 /- 6 uM。在离体兔心脏中，GR 0.003-0.03 nM 剂量依赖性地减少 s-HT 心动过速；高水平的 GR 降低了对 5-HT 的次最大和最大反应。

格拉司琼对仔猪顺铂引起的呕吐具有显着的益处，一些动物在急性期和延迟期都得到完全保护。每天给予猫 3 次格拉司琼（1 mg/kg，肌肉注射）可显着减少顺铂在第 1 天和第 2 天引起的干呕+呕吐反应，分别达 100.0% 和 75.0%。格拉司琼或地塞米松可显着改善大鼠的宏观和组织学评分，降低髓过氧化物酶活性并降低结肠炎性细胞因子和丙二醛水平。格拉司琼不仅可以防止霍乱毒素诱导的空肠净液分泌，而且还可以按比例抑制 5-HT 释放到小鼠的肠腔中。

使用已建立的5-HT3受体活性模型研究了BRL 43694（格拉司琼）的活性。在豚鼠离体回肠中，BRL 43694拮抗了相对高浓度5-羟色胺引起的收缩（pA2=8.1+/-0.2）。然而，除高浓度外，BRL 43694不影响电场刺激（胆碱能介导）、烟碱激动剂二甲基苯基哌嗪（DMPP）或八肽胆囊收缩素诱发的回肠类似制剂的收缩。同样，BRL 43694不影响大鼠或人类离体胃的电诱发、胆碱能介导的收缩。在5-HT3受体活性的其他模型中（兔离体心脏、麻醉大鼠的Bezold-Jarisch反射），BRL 43694显示出强烈的拮抗作用。在大鼠脑膜的放射配体结合研究中，BRL 43694对5-HT1A、5-HT1B、5-HT2或许多其他结合位点几乎没有亲和力。因此，BRL 43694可能是一种强效且选择性的5-HT3受体拮抗剂[Eur J Pharmacol. 1989 Jan 10;159(2):113-24.]。

在大鼠前胃中，GR 减少 5-HT 诱发的收缩，IC50 为 17 /- 6 uM。 GR 0.003-0.03 nM 剂量依赖性地降低离体兔心脏中的 s-HT 心动过速；在高浓度下，GR 降低了对 5-HT 的次最大和最大反应。

---

1.在这项研究中，研究人员研究了两种5-羟色胺3拮抗剂昂丹司琼和格拉司琼对猫离体心室肌细胞动作电位持续时间（APD）和延迟整流电流（IK）的影响。用膜片钳技术在37摄氏度下进行全细胞电流和动作电位记录。2.昂丹司琼和格拉司琼分别以1.7+/-1.0和4.3+/-1.7微M的KD阻断IK。在较高浓度（30微M）下，两种药物都阻断了内向整流器（IKl）。3.IK的阻断依赖于通道激活。这两种药物都减缓了IK尾电流的衰减，并与药物前的电流轨迹产生了交叉。这些结果与通道打开状态下的阻塞和解锁一致。4.格拉司琼显示出内在的电压依赖性，因为随着去极化，阻滞增加。阻断的等效电压依赖性（δ）为0.10+/-0.04，表明格拉司琼在跨膜电场10%的结合位点从细胞内侧阻断。5.昂丹司琼（1微M）和格拉司琼（3微M）在0.5 Hz下将APD延长了约30%。昂丹司琼对APD的延长在更快的频率（3 Hz）下被消除，显示出相反的速率依赖性。6.总之，5-羟色胺3拮抗剂昂丹司琼和格拉司琼是心室延迟整流的开放状态阻断剂，显示出明显的III类作用。

We analyzed the effects of the 5-HT3 receptor antagonist granisetron on both acute and delayed phases of cisplatin-induced emesis in the conscious piglet. Animals that received a high dose of cisplatin (5.5 mg/kg i.v.) were observed continuously for 60 h. Seventeen piglets were treated with cisplatin only and acted as controls. In experimental animals, granisetron (administered before cisplatin) was administered either as a single initial injection (7 mg/kg), alone or in combination with dexamethasone (40 mg), or as multiple injections (1 mg/kg) given every 5 h during the first 30 h of the experiment (cumulative dose: 7 mg/kg). Two other groups of piglets were treated with dexamethasone (40 mg) alone or with multiple injections of ondansetron (7 injections at 3.5 mg/kg), respectively. The latency to the first emetic episode was significantly increased in all groups that received a 5-HT3 receptor antagonist, whatever the agent and the protocol of administration. Piglets treated solely with dexamethasone exhibited a latency similar to that of controls. The total number of emetic events during the 60 h was significantly reduced only in the group of piglets treated repeatedly with granisetron and in the group that received an initial dose (7 mg/kg) of granisetron in combination with dexamethasone. We observed that 3 out of 8 piglets treated repeatedly with granisetron did not vomit throughout the experiment. These results demonstrate that granisetron, when administered repeatedly, is efficacious against delayed emesis. They also suggest that serotonin may be involved in the production of the delayed phase of cisplatin-induced emesis.[2]

---

The emetic action of cisplatin was investigated in the cat using a closed circuit video recording system. In initial investigations, cisplatin 3 and 5 mg/kg, i.v. induced emesis over a 2-day period following a latency of 17.6+/-9.6 and 15.6+/-7.8 h, respectively. The anti-emetic efficacy of granisetron and dexamethasone was investigated in the cisplatin 5 mg/kg, i.v.-induced emesis model. In these experiments, cisplatin induced 47.0+/-14.0 and 20.0+/-9.0 retches+vomits on days 1 and 2, respectively, following a latency of 2.4+/-0.4 h. Granisetron (1 mg/kg, i.m.) administered three times per day reduced significantly the retching+vomiting response induced by cisplatin on days 1 and 2 by 100.0% (P<0.05) and 75.0% (P<0.05), respectively; dexamethasone (0.01-1 mg/kg, i.m.) administered three times per day reduced significantly the retching+vomiting response by 68.8-100.0% (P<0.05) and 33.3-100.0% (P<0.05) on days 1 and 2, respectively. The emetic action of cisplatin 7.5 mg/kg, i.v. was also investigated. This dose of cisplatin-induced emesis following a latency of 1.2+/-0.2 h and comprised 119.0+/-20.8 retches+vomits over a 24-h period. Granisetron and dexamethasone antagonized the emesis occurring in the first 3-h period (P<0.05) but were less effective to antagonize the subsequent emetic response (P0.05). The pharmacological sensitivity of low dose cisplatin-induced emesis in the cat is variable but unique and not representative of the clinical situation.[3]

---

Inflammatory bowel disease (IBD) is a chronically relapsing inflammation of the gastrointestinal tract, of which the definite etiology remains ambiguous. Considering the adverse effects and incomplete efficacy of currently administered drugs, it is indispensable to explore new candidates with more desirable therapeutic profiles. 5-HT( 3) receptor antagonists have shown analgesic and anti-inflammatory properties in vitro and in vivo. This study aims to investigate granisetron, a 5-HT( 3) receptor antagonist, in acetic acid-induced rat colitis and probable involvement of 5-HT(3) receptors. Colitis was rendered by instillation of 1 mL of 4% acetic acid (vol/vol) and after 1 hour, granisetron (2 mg/kg), dexamethasone (1 mg/kg), meta-chlorophenylbiguanide (mCPBG, 5 mg/kg), a 5-HT( 3) receptor agonist, or granisetron + mCPBG was given intraperitoneally. Twenty-four hours following colitis induction, animals were sacrificed and distal colons were assessed macroscopically, histologically and biochemically (malondialdehyde, myeloperoxidase, tumor necrosis factor-alpha, interleukin-1 beta and interleukin-6). Granisetron or dexamethasone significantly (p < .05) improved macroscopic and histologic scores, curtailed myeloperoxidase activity and diminished colonic levels of inflammatory cytokines and malondialdehyde. The protective effects of granisetron were reversed by concurrent administration of mCPBG. Our data suggests that the salutary effects of granisetron in acetic acid colitis could be mediated by 5-HT(3) receptors.[4]

---

1 mg/kg, i.m.

Piglet

Absorption, Distribution and Excretion
Absorption
Absorption of is rapid and complete, though oral bioavailability is reduced to about 60% as a result of first pass metabolism.

Route of Elimination
The remainder of the dose is excreted as metabolites, 48% in the urine and 38% in the feces.

Clearance
0.52 L/h/kg [Cancer Patients with 1 mg bid for 7 days]
0.41 L/h/kg [Healthy subject with a single 1 mg dose]

---

Metabolism / Metabolites
Primarily hepatic; undergoes N -demethylation and aromatic ring oxidation followed by conjugation. Animal studies suggest that some of the metabolites may have 5-HT 3 receptor antagonist activity.
Granisetron has known human metabolites that include 9'-Desmethylgranisetron and 7-Hydroxygranisetron.

---

Biological Half-Life
4-6 hours in healthy patients, 9-12 hours in cancer patients

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of granisetron during breastfeeding. Until more data become available, granisetron should be used with caution during breastfeeding. An alternate drug may be preferred.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
A woman nursing an 8-month-old infant 6 to 8 times daily was admitted to the hospital for an appendectomy. During the procedure she received granisetron, cefazolin, ketorolac, rocuronium, succinylcholine, and sufentanil. The patient also received 2 boluses of intravenous propofol of 150 mg followed shortly thereafter by a 50 mg dose. Postoperatively, she was receiving acetaminophen, cefazolin, ibuprofen, and pantoprazole, as well as oxycodone and dimenhydrinate as needed. Twenty-two hours after the procedure, the mother extracted milk for the first time and noted it to be light green in color. Analysis of the green milk using a nonvalidated assay detected no propofol. The green color faded and was absent by postoperative day 4 when she resumed breastfeeding. The authors judged that the green color was possibly caused by propofol or one of its metabolites.

[1]. Br J Pharmacol . 1994 Oct;113(2):527-35.

[2]. J Pharmacol Exp Ther . 1996 Oct;279(1):255-61.

[3]. Eur J Pharmacol . 2000 Mar 10;391(1-2):145-50.

[4]. Hum Exp Toxicol . 2010 Apr;29(4):321-8.

[5]. Br J Pharmacol . 2000 Jul;130(5):1031-6.

Granisetron hydrochloride is an aromatic amide and a member of indazoles.
A serotonin receptor (5HT-3 selective) antagonist that has been used as an antiemetic for cancer chemotherapy patients.
See also: Granisetron Hydrochloride (annotation moved to).

---

Drug Indication
Prevention of nausea and vomiting in patients receiving moderately or highly emetogenic chemotherapy, with or without cisplatin, for up to five consecutive days. Sancuso may be used in patients receiving their first chemotherapy regimen or in patients who have previously received chemotherapy.

C18H25CLN4O

348.87

348.171

C, 61.97; H, 7.22; Cl, 10.16; N, 16.06; O, 4.59

107007-99-8

Granisetron; 109889-09-0; 107007-99-8 (HCl)

6918003

White solid powder

1.33g/cm3

532ºC at 760mmHg

290-292°C

275.6ºC

0mmHg at 25°C

1.69

3.449

50.16

2

3

2

24

442

2

Cl[H].O=C(C1C2=C([H])C([H])=C([H])C([H])=C2N(C([H])([H])[H])N=1)N([H])C1([H])C([H])([H])[C@@]2([H])C([H])([H])C([H])([H])C([H])([H])[C@@]([H])(C1([H])[H])N2C([H])([H])[H]

QYZRTBKYBJRGJB-UHFFFAOYSA-N

InChI=1S/C18H24N4O.ClH/c1-21-13-6-5-7-14(21)11-12(10-13)19-18(23)17-15-8-3-4-9-16(15)22(2)20-17;/h3-4,8-9,12-14H,5-7,10-11H2,1-2H3,(H,19,23);1H

1-methyl-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)indazole-3-carboxamide;hydrochloride

BRL43694; BRL 43694; BRL43694A; BRL 43694A; BRL-43694; BRL-43694A; Granisetron Hydrochloride; Granisetron hydrocholride,(S); 1-methyl-N-((1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-1H-indazole-3-carboxamide hydrochloride; Granisetron HCl; GRAN; US trade name: Kytril

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: ≥ 0.77 mg/mL (2.21 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 7.7 mg/mL澄清的DMSO储备液加入到400 μL PEG300中，混匀；再向上述溶液中加入50 μL Tween-80，混匀；然后加入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。

---

配方 2 中的溶解度: ≥ 0.77 mg/mL (2.21 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 7.7 mg/mL 澄清 DMSO 储备液加入900 μL 玉米油中，混合均匀。

---

View More

配方 3 中的溶解度: 100 mg/mL (286.64 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.

---

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。