5-HT3 Receptor ( IC50 = 17 μM )
Granisetron is a 5-HT3 receptor antagonist.

GR exhibited an IC50 of 17/± 6 uM in rat forestomach, reducing 5-HT-induced contractions. GR decreased s-HT tachycardia in isolated rabbit hearts in a dose-dependent manner with a range of 0.003-0.03 nM; high GR levels also decreased submaximal and maximum responses to 5-HT [1].

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In guinea-pig isolated ileum, granisetron (0.01 - 1.0 μM) antagonised contractions evoked by higher concentrations of 5-HT in an apparently competitive manner, with a pA2 value of 8.1 ± 0.2 (slope of Arunlakshana and Schild plot = 1.0 ± 0.1). Contractions evoked by lower concentrations of 5-HT were unaffected. [1]
Granisetron (0.1 and 1.0 μM) did not significantly affect DMPP-evoked contractions of guinea-pig ileum, whereas 10 μM caused a reduction (estimated pD2' = 4.8 ± 0.3). [1]
Except in high concentrations (100 μM), granisetron had no effects on electrically evoked, cholinergically mediated contractions of guinea-pig ileum, rat forestomach, or human stomach. [1]
In guinea-pig ileum, the potentiation of electrically evoked contractions caused by 5-HT was unaffected by granisetron (1.0 μM). The decrease in height of EFS-evoked contractions caused by 8-OH-DPAT was unaffected by granisetron (1.0 μM; dose-ratio = 1.4 ± 0.8). [1]
In rat forestomach, only high concentrations of granisetron reduced 5-HT-evoked contractions (1 nM - 100 μM tested; IC50 = 17 ± 6 μM). [1]
In rat brain membranes, granisetron had little or no affinity for 5-HT1A (Ki = 6.9 μM), 5-HT1B (Ki > 10 μM), 5-HT2 (Ki > 6.3 μM), dopamine D1 and D2, histamine H1, benzodiazepine, picrotoxin-sensitive chloride channel, or α1, α2, and β-adrenoceptor binding sites. [1]

Six and 72 hours after the development of inflammation, granisetron dose-dependently reduced leukocyte accumulation. PGE(2) levels were elevated by Granisetron at lower dosages (50 μg/bag), but release was suppressed at higher doses (100 and 200 μg/bag). Concurrently, granisetron at lower doses will decrease TNFα production, but granisetron at higher doses will enhance TNFα production; these two effects are reciprocal [2]. It was demonstrated that GTDS was not inferior to oral granisetron: 65% of patients receiving oral granisetron and 60% of patients receiving GTDS obtained complete control (treatment difference, -5%; 95% confidence range, -13-3). Constipation was the most frequent side effect of both well-tolerated therapies [3].

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In anaesthetised rats, granisetron (0.1-10.0 μg/kg i.v.) had no effects on resting blood pressure or heart rate but reduced the 5-HT-evoked Bezold-Jarisch reflex. The ID50 (dose required to reduce effects of 5-HT by 50%) was 0.7 ± 0.2 μg/kg i.v. Intraduodenal injection of a single dose of granisetron (100 or 500 μg/kg) dose-dependently reduced or caused a long-lasting abolition of the Bezold-Jarisch reflex. Granisetron (100 μg/kg i.v.) did not affect bradycardia caused by electrical stimulation of the vagus (5-30 Hz). [1]
In the rat air-pouch model of inflammation, intra-pouch injection of granisetron (50, 100, and 200 μg/pouch) dose-dependently inhibited leukocyte accumulation at both 6 hours (cell counts: 6.25×10^7, 6.95×10^7, 8.25×10^7 vs control 11.71×10^7) and 72 hours (cell counts: 7.21×10^7, 6.72×10^7, 5.69×10^7 vs control 11.16×10^7) after carrageenan injection. Granulation tissue weight was not changed. [2]
Granisetron (50, 100, and 200 μg/pouch) decreased hemoglobin level in whole granulation tissue, indicating inhibition of angiogenesis, in a bell-shaped manner. Vascular network formation was also inhibited by granisetron (100 μg). [2]
In the same model, granisetron (50 μg/pouch) increased PGE2 level (to 6159±652 pg/ml vs control 5366±712 pg/ml) and decreased TNFα concentration (to 26±8 pg/ml vs control 118±24 pg/ml). At higher doses (100 and 200 μg/pouch), granisetron decreased PGE2 (2985±218 and 2967±672 pg/ml) and increased TNFα (71±10 and 172±28 pg/ml). [2]
In a randomized, double-blind, phase III study, transdermal granisetron (GTDS, one patch delivering 34.3 mg over 7 days) was non-inferior to oral granisetron (2 mg/day for 3-5 days) for complete control of CINV (no vomiting/retching, no more than mild nausea, no rescue medication) in patients receiving multi-day chemotherapy. Complete control was achieved by 60% of patients in the GTDS group and 65% in the oral granisetron group (treatment difference -5%; 95% CI -13 to 3). [3]

The activity of BRL 43694 (granisetron) was investigated using established models of 5-HT3 receptor activity. In guinea-pig isolated ileum, BRL 43694 antagonised the contractions evoked by relatively high concentrations of 5-HT (pA2 = 8.1 +/- 0.2). However, except in high concentrations, BRL 43694 did not affect the contractions of similar preparations of ileum, evoked by electrical field stimulation (cholinergically mediated), the nicotinic agonist dimethylphenyl piperazinium (DMPP) or by cholecystokinin octapeptide. Similarly, BRL 43694 did not affect electrically evoked, cholinergically mediated contractions of rat or human isolated stomach. In other models of 5-HT3 receptor activity (rabbit isolated heart, Bezold-Jarisch reflex in anaesthetised rats), potent antagonism by BRL 43694 was demonstrated. In radioligand binding studies on rat brain membranes, BRL 43694 had little or no affinity for 5-HT1A, 5-HT1B, 5-HT2 or for many other binding sites. BRL 43694 may therefore be a potent and selective 5-HT3 receptor antagonist[1].

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Displacement of 3H-ligand binding to rat brain membranes was determined using a range of five duplicate drug concentrations between 10^-9 and 10^-4 M. Incubations were terminated by rapid filtration through glass-fibre filters under reduced pressure and rinsed with ice-cold buffer. Radioactivity was measured by liquid scintillation spectrometry. Specific binding was defined as the difference between total counts obtained in the presence and absence of an excess of unlabelled specific ligand. IC50 values were obtained from inhibition curves and apparent Ki values were determined from the equation Ki = IC50/(1 + C/Kd) where C = concentration of radiolabel and Kd = affinity constant. [1]

For the guinea-pig isolated ileum, longitudinal muscle-myenteric plexus preparations were suspended under a 0.5 g load in tissue baths. Concentration-response curves for 5-HT were constructed by adding increasing concentrations every 15 min with 60 s contact times for low concentrations (0.003 - 1.3 μM) and 30 s contact times for higher concentrations (3 μM - 1.3 mM). The heights of the 5-HT-evoked contractions were calculated as a percentage of a previously obtained maximum acetylcholine-evoked contraction. Methysergide (0.2 μM) was routinely added to block non-neuronal actions of 5-HT. [1]
For the rat isolated forestomach, concentration-response curves were constructed for 5-HT with atropine (1.4 μM) continually present. Concentrations of 5-HT were chosen to give contractions approximately 50% of maximum (1.3 - 2.6 nM; 90 s contacts, 15 min cycle). [1]
For the rabbit isolated heart, the ability of 5-HT to stimulate noradrenergic neurones was evaluated by measuring resultant tachycardia. Coronary arteries were perfused with Krebs solution containing atropine (1.4 μM). Dose-response curves to 5-HT were constructed by bolus injections of increasing doses into the perfusate every 5-10 min. [1]

The antagonists of 5HT(3) receptors have shown impressive efficacy in rheumatoid arthritis, osteoarthritis or fibromyalgia. The mechanistic relationships between 5HT(3) receptors, angiogenesis and sequence of cytokine expression, and leukocyte recruitment during inflammation are not clear. We evaluate the effects of granisetron on inflammatory parameters and angiogenesis in rat air-pouch model. Methods: Male Wistar rats were anesthetized, and then 20 ml and 10 ml of sterile air were injected subcutaneously in the back on day 0 and day 3, respectively. On day 6, inflammation was induced by injection of 1 ml of carrageenan 1% into pouches. After 6 and 72 h, the rats were sacrificed; pouch fluid was collected in order to determine exudate volume, the number of accumulated cells and TNFalpha/PGE(2) concentration. Pouches were dissected out and weighed. Angiogenesis of granulomatous tissue was assayed using a hemoglobin kit. Results: Leukocyte accumulation was dose-dependently inhibited by granisetron both at 6 and 72 h after induction of inflammation. All doses of granisetron decreased hemoglobin level in the whole granulation tissue in a bell-shaped manner. Vascular network formation was also inhibited by granisetron. Granisetron increased PGE(2) level at a lower dose (50 microg/pouch) but higher doses (100 and 200 microg/pouch) inhibited the release. At the same time, TNFalpha production was decreased by the lower dose and increased by higher doses of granisetron in a reciprocal fashion. Conclusions: Anti-inflammatory activities of 5HT(3) receptor antagonist, granisetron probably are mediated through modulation of TNFalpha/PGE(2) production and leukocyte infiltration[2].

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In anaesthetised rats, the Bezold-Jarisch effect was evoked by rapid, bolus intravenous injections of 5-HT, using the minimum dose which evoked a clear bradycardia (6-30 μg/kg, usually 15 μg/kg). Injections of 5-HT were given every 12 min and a dose-response curve for granisetron was established by injecting increasing doses of compound 5 min before each injection of 5-HT. In separate experiments, a single dose of granisetron was injected (0.2 ml volumes) into the duodenum via a previously inserted cannula. [1]
To induce an air-pouch in rats, 20 ml of sterile air was injected subcutaneously in the back on day 0 and 10 ml on day 3. On day 6, inflammation was induced by injection of 1 ml of carrageenan 1% into pouches. Granisetron (50, 100, and 200 μg/pouch) or vehicle dissolved in 500 μl of saline was injected into the pouch just after carrageenan injection (6 h study) and then once a day on two consecutive days (72 h study). At 6 and 72 h, rats were sacrificed; pouch fluid was collected to determine exudate volume, number of accumulated cells, and TNFα/PGE2 concentration. Pouches were dissected and weighed. Angiogenesis was assayed using a hemoglobin kit. [2]
In a phase III study, patients received either a granisetron transdermal system (GTDS) patch applied to the upper arm 24-48 h before chemotherapy and left in place for 7 days, or oral granisetron (2 mg) administered 1 h before each day's chemotherapy for 3-5 days. Corticosteroids were permitted at the discretion of the investigator as prophylaxis. Rescue medication was permitted. [3]

Absorption, Distribution and Excretion
This product is rapidly and completely absorbed, but oral bioavailability is reduced to approximately 60% due to first-pass metabolism. The remaining dose is excreted as metabolites, with 48% excreted in the urine and 38% in the feces. 0.52 L/h/kg [Cancer patients, 1 mg twice daily for 7 days] 0.41 L/h/kg [Health subjects, 1 mg single dose] Metabolism/Metabolites Primarily metabolized in the liver; undergoes N-demethylation and aromatic epoxidation, followed by a conjugation reaction. Animal studies have shown that some metabolites may have 5-HT3 receptor antagonistic activity. Known metabolites of granisetron include 7-hydroxygranisetron and 9'-demethylgranisetron. Biological Half-Life 4–6 hours in healthy subjects, 9–12 hours in cancer patients.

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Pharmacokinetic evaluation of the GTDS indicates that it provides continuous delivery of granisetron over 7 days, providing exposure similar to an oral dose of 2 mg per day. [3]

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
There is currently no information on the use of granisetron during lactation. Until more data becomes available, granisetron should be used with caution during lactation. Alternative medications are recommended.
◉ Effects on Breastfed Infants
As of the revision date, no relevant published information was found.
◉ Effects on Lactation and Breast Milk
A woman who breastfed an 8-month-old infant 6 to 8 times daily was admitted for an appendectomy. During the surgery, she received granisetron, cefazolin, ketorolac, rocuronium bromide, succinylcholine, and sufentanil. The patient also received two intravenous boluses of 150 mg propofol, followed shortly by an intravenous bolus of 50 mg propofol. Postoperatively, she took acetaminophen, cefazolin, ibuprofen, and pantoprazole, and oxycodone and dimenhydrinate as needed. Twenty-two hours post-surgery, the mother expressed breast milk for the first time, finding it to be light green. Analysis of the green milk using an unverified testing method yielded no detectable propofol. The green color gradually faded, disappearing by the time she resumed breastfeeding on the fourth day post-surgery. The authors believe the green color was likely caused by propofol or its metabolites.

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Protein binding
65%

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In the phase III study, both transdermal and oral granisetron were well tolerated. The most common treatment-related adverse event was constipation, reported more frequently with GTDS (7%) than oral granisetron (3%). Headache was reported more frequently with oral granisetron (2.5%) than GTDS (0.3%). Application site pruritus was reported in two cases (GTDS group). Serious TEAEs considered study drug-related included QTc prolongation (n=3) and toxic megacolon (n=1) in the oral granisetron group, and constipation (n=1) in the GTDS group. No cases of QTc prolongation were identified in the GTDS group. [3]

[1]. Sanger GJ, Nelson DR. Selective and functional 5-hydroxytryptamine3 receptor antagonism by BRL 43694 (granisetron). Eur J Pharmacol. 1989 Jan 10;159(2):113-24.

[2]. Maleki-Dizaji N, Eteraf-Oskouei T, Fakhrjou A, The effects of 5HT3 receptor antagonist granisetron on inflammatory parameters and angiogenesis in the air-pouch model of inflammation. Int Immunopharmacol. 2010 Sep;10(9):1010-6.

[3]. Boccia RV, Gordan LN, Clark G, Efficacy and tolerability of transdermal granisetron for the control of chemotherapy-induced nausea and vomiting associated with moderately and highly emetogenic multi-day chemotherapy: a randomized, double-blind, phase III.

Granisetron is a monocarboxylic acid amide formed by the condensation of the carboxyl group of 1-methyl-1H-indazole-3-carboxylic acid with the primary amino group of (3-endo)-9-methyl-9-azabicyclo[3.3.1]nonane-3-amine. It is a selective 5-HT3 receptor antagonist, commonly used in hydrochloride form to treat nausea and vomiting induced by chemotherapy and radiotherapy in cancer, as well as to prevent and treat postoperative nausea and vomiting. It has the effects of a serotonergic antagonist and an antiemetic. It belongs to the indazole class of compounds and is a monocarboxylic acid amide and tertiary amine compound.
Granisetron is a selective serotonin receptor (5-HT3) antagonist and has been used as an antiemetic and antiemetic agent for cancer chemotherapy patients.
Granisetron is a serotonin-3 receptor antagonist. Granisetron's mechanism of action is as a serotonin-3 receptor antagonist.
Granisetron is an indazole derivative with antiemetic properties. As a selective serotonin receptor antagonist, granisetron inhibits nausea and vomiting induced by chemotherapy and radiotherapy by competitively blocking the binding of serotonin to the serotonin 3 (5-HT3) receptor. APF530 is a controlled-release formulation of a biodegradable polyorthoester polymer encapsulating granisetron, an indazole derivative with antiemetic activity. After administration of APF530, the polymer slowly degrades and releases the active ingredient, granisetron. As a selective serotonin receptor antagonist, granisetron sustainably inhibits nausea and vomiting by competitively blocking the binding of serotonin to the serotonin 3 (5-HT3) receptor. A selective serotonin receptor antagonist has been used for antiemetic treatment in cancer chemotherapy patients. See also: granisetron (note moved to). Drug Indications For the prevention of nausea and vomiting associated with initial and repeated emetogenic cancer treatments (including high-dose cisplatin), postoperative care, and radiation therapy (including total body irradiation and daily fractionated abdominal irradiation). FDA Label For the prevention of nausea and vomiting over five consecutive days in patients receiving moderate to highly emetogenic chemotherapy (with or without cisplatin). Sancuso may be used in patients receiving their first chemotherapy or in patients who have previously received chemotherapy. Mechanism of Action Granisetron is a potent, selective 5-HT3 receptor antagonist. Its antiemetic effect is achieved by inhibiting 5-HT3 receptors present in both the central (medullobulatory chemoreceptor area) and peripheral (gastrointestinal) regions. This inhibition of 5-HT3 receptors, in turn, inhibits visceral afferent stimulation of the vomiting center, possibly through indirect action on the postmedullobulatory region and direct inhibition of serotonin activity in the postmedullobulatory region and chemoreceptor trigger zone.

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Pharmacodynamics
Granisetron is a selective inhibitor of the type 3 serotonin (5-HT3) receptor. Granisetron has little affinity for other serotonin receptors (including 5-HT1, 5-HT1A, 5-HT1B/C, or 5-HT2 receptors), α1, α2, or β-adrenergic receptors, dopamine D2 receptors, histamine H1 receptors, benzodiazepine receptors, bitter glycoside receptors, or opioid receptors. In most human studies, granisetron has had minimal effects on blood pressure, heart rate, or electrocardiogram (ECG). This drug is structurally and pharmacologically related to ondansetron (another selective 5-HT3 receptor inhibitor).
Serotonin 5-HT3 receptors are located at peripheral vagal nerve endings and in the chemoreceptor trigger zone of the postmedula medulla oblongata. The temporal relationship between the emetic effect of emetic drugs and serotonin release, as well as the efficacy of antiemetics, suggests that chemotherapeutic drugs induce serotonin release from intestinal chromaffin cells by causing degenerative changes in the gastrointestinal tract. Serotonin then stimulates vagal and visceral nerve receptors projecting to the medullary vomiting center, as well as 5-HT3 receptors in the postmedula medulla oblongata, thereby initiating the vomiting reflex and inducing nausea and vomiting.

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Granisetron (BRL 43694) is a potent and selective 5-HT3 receptor antagonist. It antagonises neuronally mediated actions of 5-HT within the peripheral nervous system. The results support the concept that 5-HT may cause contraction of guinea-pig isolated ileum by activating two different mechanisms. [1]
Granisetron has anti-inflammatory activities probably mediated through modulation of TNFα/PGE2 production and leukocyte infiltration. The anti-angiogenic effect of granisetron can be considered a promising action in treating cancer and chronic inflammatory diseases. [2]
The granisetron transdermal system (GTDS) is indicated for the control of chemotherapy-induced nausea and vomiting (CINV) associated with moderately or highly emetogenic multi-day chemotherapy. It offers a convenient non-invasive option for sustained antiemetic administration, reducing pill burden and potentially improving compliance. [3]

C18H24N4O

312.40936

312.195

C, 69.20; H, 7.74; N, 17.93; O, 5.12

109889-09-0

Granisetron Hydrochloride;107007-99-8;Granisetron-d3;1224925-64-7

5284566

White to off-white solid powder

1.3±0.1 g/cm3

532.0±40.0 °C at 760 mmHg

219 °C (hydrochloride salt)

275.6±27.3 °C

0.0±1.4 mmHg at 25°C

1.690

1.47

1

3

2

23

442

2

CN1[C@@H]2CCC[C@H]1CC(C2)NC(=O)C3=NN(C4=CC=CC=C43)C

MFWNKCLOYSRHCJ-AGUYFDCRSA-N

InChI=1S/C18H24N4O/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)/t12?,13-,14+

1-methyl-N-[(1R,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl]indazole-3-carboxamide

granisetron; 109889-09-0; Sancuso; Sustol; Kevatril; BRL-43694; Granisetronum; APF530;

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)

DMSO : ~25 mg/mL (~80.02 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.00 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 (8.00 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 (8.00 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.)