| Size | Price | Stock | Qty |
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Purity: ≥98%
Palonosetron (formerly RS-25259, RS-25259 197; trade name: Aloxi and Akynzeo) is a 5-HT3 antagonist approved for use in the prevention and treatment of chemotherapy-induced nausea and vomiting. As of April 2018, the combination of fosnetupitant and palonosetron was approved by FDA to prevent acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Palonosetron is a highly potent, selective, second-generation 5-HT3 receptor antagonist with a 5-HT3 receptor binding affinity that is ∼100-fold higher than other 5-HT3 receptor antagonists (pKi 10.5 compared with 8.91 for granisetron, 8.81 for tropisetron, 8.39 for ondansetron, 7.6 for dolasetron).
| Targets |
5-HT3 Receptor ( Ki = 0.17 nM )
In vitro activity: Palonosetron is an antagonist that binds to the 5-HT3 receptor very well, and it has little to no affinity for other receptors[1]. |
|---|---|
| ln Vitro |
In vitro activity: Palonosetron is an antagonist that binds to the 5-HT3 receptor very well, and it has little to no affinity for other receptors[1].
Palonosetron demonstrated a 5-HT3 receptor binding affinity at least 30-fold higher than other first-generation 5-HT3 receptor antagonists. It exhibited allosteric binding and positive cooperativity when binding to the 5-HT3 receptor, in contrast to the simple bimolecular binding of granisetron and ondansetron. [1] Palonosetron did not inhibit the antitumor activity of five chemotherapeutic agents (cisplatin, cyclophosphamide, cytarabine, doxorubicin, and mitomycin C) in murine tumor models. [1] |
| ln Vivo |
Palonosetron surpasses the first-generation 5-HT3 receptor antagonists in both half-life and binding affinity. When palonosetron is given intravenously to both healthy individuals and cancer patients, the body gradually eliminates the drug after an initial drop in plasma concentration. Between 0.3 and 90 μg/kg, the mean maximum plasma concentration and the area under the concentration-time curves in both healthy individuals and cancer patients are typically dose-proportional. With a volume of distribution of 8.3 ± 2.5 L/kg, palonosetron is 62% bound to plasma proteins. Through metabolic processes and renal excretion, it is removed from the body. 40 hours is roughly the mean terminal elimination half-life[1].
In animal studies, chemotherapy-induced nausea and vomiting are initiated by serotonin release from enterochromaffin cells, which activates 5-HT3 receptors on vagal afferents. Palonosetron binds to these receptors with high affinity to inhibit the vomiting reflex. [1] |
| Enzyme Assay |
Palonosetron is a second-generation, highly selective, potent antagonist of the 5-HT3 receptor with a binding affinity for the receptor that is approximately 100 times higher than that of other antagonists of the 5-HT3 receptor (pKi 10.5 compared with 8.91 for granisetron, 8.81 for tropisetron, 8.39 for ondansetron, and 7.6 for dolasetron).
Palonosetron exhibits a high binding affinity for the 5-HT3 receptor with a pKi of 10.45, compared to ondansetron (pKi = 8.39), granisetron (pKi = 8.91), and dolasetron (pKi = 7.60). Binding studies indicate that palonosetron binds allosterically and shows positive cooperativity, whereas granisetron and ondansetron exhibit simple bimolecular binding. This difference in binding behavior may contribute to its distinct clinical efficacy, particularly in delayed CINV. [1] |
| Cell Assay |
Palonosetron is a 5-HT3 antagonist used to treat and prevent nausea and vomiting brought on by chemotherapy (CINV). IC50 Value: Among the 5-HT3 antagonists, 5-HT3 Receptor Palonosetron is the most successful in managing delayed CINV nausea and vomiting that manifests over a 24-hour period following the initial dosage of a chemotherapy regimen.
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| Animal Protocol |
Autoradiographical studies[3]
Coronal sections of rat and mouse brains were cut at 20 ,um thickness. Sections were dried and pre-incubated in Tris-HCl buffer (50 mM Tris, 120 mM NaCl, pH 7.4, 22°C) for 30 min. The sections were then covered with the same buffer contain- -4 ing 1.0 nM [3H]-RS 42358-197 or [3H]-RS 25259-197 for 60 min at 22°C. Non-specific binding was defined in the presence of 1.0 tLM (S)-zacopride. The incubations were ter- -n minated by rinsing the slides for two washes of 5 min in ice cold buffer. The sections were dried and apposed, together with 3H polymer standards (Amersham, Inc.) to tritiumsensitive X-ray film for 24 weeks. The autoradiograms were then analysed by digital image analysis with the MCID imaging system (Imaging Research, Inc.). Brain areas were verified on cresyl violet stained sections after autoradiography, using the areas described in the rat brain atlas of Paxinos & Watson (1985). In a murine tumor model, palonosetron was evaluated for potential interference with the antitumor activity of various chemotherapeutic agents (cisplatin, cyclophosphamide, cytarabine, doxorubicin, mitomycin C). No inhibition of antitumor efficacy was observed. [1] In a clinical study setting for postoperative nausea and vomiting (PONV), a single intravenous dose of 0.075 mg palonosetron was administered prior to surgery. [1] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Oral bioavailability is low. Following a single intravenous injection of 10 mcg/kg [14C]-palonosetron, approximately 80% of the dose is excreted in the urine within 144 hours. 8.3 ± 2.5 L/kg 160 ± 35 mL/h/kg Metabolism/Metabolites Hepatic metabolism (50%), primarily mediated by CYP2D6, but also by CYP3A4 and CYP1A2. Biological Half-Life Approximately 40 hours Following intravenous administration, the mean terminal elimination half-life of palonosetron is approximately 40 hours. [1] Volume of distribution is approximately 8.3 ± 2.5 L/kg. Plasma protein binding is 62%. [1] Palonosetron is primarily eliminated via renal excretion and metabolism. Approximately 80% of the drug is excreted in the urine within 144 hours after a single intravenous injection, of which approximately 40% is the original drug. [1] Approximately 50% of palonosetron is primarily metabolized by CYP2D6, with smaller amounts metabolized by CYP3A and CYP1A2, producing two major metabolites. The 5-HT3 receptor antagonistic activity of each metabolite is less than 1% of that of the original drug. [1] There were no significant differences in pharmacokinetic parameters between patients with weak and strong CYP2D6 metabolism. [1] Mild to moderate renal or hepatic impairment had no significant effect on the pharmacokinetics of palonosetron; no dose adjustment was required. [1] Population pharmacokinetic analysis showed no significant difference between patients ≥65 years of age and younger patients. [1] |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation
◉ Overview of use during lactation There is currently no information on the use of palonosetron during lactation. Palonosetron should be used with caution during lactation until more data are available. It is recommended to prioritize other medications. ◉ Effects on breastfed infants No relevant published information was found as of the revision date. ◉ Effects on lactation and breast milk No relevant published information was found as of the revision date. 62% The most common adverse reactions to palonosetron are headache and constipation, consistent with the adverse reactions of 5-HT3 receptor antagonists. The incidence of all other adverse reactions is ≤1%. [1] No clinically significant differences were observed in laboratory tests, electrocardiograms, or changes in vital signs among palonosetron, ondansetron, and dolasetron. [1] A volunteer clinical study showed that the cardiac effects of palonosetron were the same as placebo, and no electrocardiographic abnormalities (including QTc interval prolongation) were observed at intravenous doses up to 2.25 mg (9 times the approved dose). [1] Palonosetron is safe for use in patients with a history of cardiac dysfunction. [1] Safety was maintained during repeated chemotherapy cycles, and the incidence of adverse events was not increased. [1] Palonosetron is not an inhibitor or inducer of major CYP enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, CYP3A4/5), suggesting a low likelihood of clinically significant drug interactions. [1] |
| References |
[3]. Br J Pharmacol. 1995 Feb;114(4):851-9.
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| Additional Infomation |
Pharmacodynamics
Palonosetron is an antiemetic used to prevent nausea and vomiting induced by moderately emetogenic chemotherapy in cancer patients, as well as postoperative nausea and vomiting. Palonosetron is a highly specific and selective serotonin (5-HT3) receptor antagonist, whose pharmacological action is related to other 5-HT3 receptor antagonists but structurally different. Palonosetron has a high affinity for the 5-HT3 receptor, while having low or no affinity for other receptors. The 5-HT3 receptor is located at peripheral vagal nerve endings and in the chemoreceptor trigger zone of the postmedulatal medulla oblongata. Studies have shown that chemotherapy drugs induce degenerative changes in the gastrointestinal tract, leading to the release of serotonin from chromaffin cells in the small intestine. Serotonin then stimulates vagal and visceral nerve receptors projecting to the medullary vomiting center, as well as 5-HT3 receptors in the postmedullary region, thereby initiating the vomiting reflex and causing nausea and vomiting. Palonosetron is a second-generation 5-HT3 receptor antagonist approved for the prevention of acute chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderate or high emetogenic chemotherapy (MEC/HEC), and for the prevention of delayed CINV in patients receiving MEC. [1] Compared to first-generation 5-HT3 receptor antagonists, palonosetron has a longer half-life (approximately 40 hours), higher receptor binding affinity, and superior efficacy in controlling delayed chemotherapy-induced nausea and vomiting (CINV), especially when used in combination with dexamethasone. [1] Palonosetron is also approved for the prevention of postoperative nausea and vomiting (PONV). [1] It shows potential for improved CINV control when used in combination with dexamethasone, aprepitant (an NK-1 receptor antagonist), and olanzapine. [1] Due to its effectiveness in both acute and late-onset phases, palonosetron has high potential for use in multi-day chemotherapy and bone marrow transplantation. [1] |
| Molecular Formula |
C19H24N2O
|
|---|---|
| Molecular Weight |
296.41
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| Exact Mass |
296.188
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| Elemental Analysis |
C, 76.99; H, 8.16; N, 9.45; O, 5.40
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| CAS # |
135729-61-2
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| Related CAS # |
Palonosetron hydrochloride; 135729-62-3; (R,R)-Palonosetron Hydrochloride; 135729-75-8
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| PubChem CID |
6337614
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| Appearance |
Solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
470.4±45.0 °C at 760 mmHg
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| Flash Point |
209.5±21.1 °C
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| Vapour Pressure |
0.0±1.2 mmHg at 25°C
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| Index of Refraction |
1.646
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| LogP |
2.61
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
2
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
22
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| Complexity |
456
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| Defined Atom Stereocenter Count |
2
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| SMILES |
O=C1N(C[C@@]([H])(CCC2)C3=C2C=CC=C13)[C@@H]4CN5CCC4CC5
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| InChi Key |
CPZBLNMUGSZIPR-NVXWUHKLSA-N
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| InChi Code |
InChI=1S/C19H24N2O/c22-19-16-6-2-4-14-3-1-5-15(18(14)16)11-21(19)17-12-20-9-7-13(17)8-10-20/h2,4,6,13,15,17H,1,3,5,7-12H2/t15-,17-/m1/s1
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| Chemical Name |
(3aS)-2-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-3a,4,5,6-tetrahydro-3H-benzo[de]isoquinolin-1-one
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| Synonyms |
RS 25259; RS 25259 197; RS 25233-197; RS25233-197; RS-25233-197; RS25233-198; RS-25233-198; RS 25233-198; RS-25259-197; Palonosetron; US brand name: Aloxi; Akynzeo
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.3737 mL | 16.8685 mL | 33.7371 mL | |
| 5 mM | 0.6747 mL | 3.3737 mL | 6.7474 mL | |
| 10 mM | 0.3374 mL | 1.6869 mL | 3.3737 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
A Phase II Trial of Neoadjuvant Laparoscopic Hyperthermic Intraperitoneal Chemotherapy (HIPEC) With Chemoradiation
CTID: NCT04308837
Phase: Phase 2 Status: Recruiting
Date: 2023-11-14
Products are for research use only; We do not sell to patients
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