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| 25mg |
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Purity: ≥98%
(R,R)-Palonosetron Hydrochloride is the active R,R-enantiomer of Palonosetron HCl (RS25259, RS-25259 197; trade name: Aloxi and Akynzeo) which is a 5-HT3 antagonist approved in 2018 in the prevention and treatment of chemotherapy-induced nausea and vomiting. Fosnetupitant and palonosetron together have been approved by the FDA in April 2018 to prevent acute and delayed nausea and vomiting that is linked to first- and second-course highly emetogenic cancer chemotherapy. 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).
| Targets |
5-HT3 Receptor
In vitro activity: 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). Additionally, palonosetron has an extended plasma elimination half-life of about 40 hours, which is substantially longer than that of other drugs in its class (ranisetron, 8.9 hours; tropisetron, 7.3 hours; dolasetron, 7.5 hours). |
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| ln Vitro |
In vitro activity: 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). Additionally, palonosetron has an extended plasma elimination half-life of about 40 hours, which is substantially longer than that of other drugs in its class (ranisetron, 8.9 hours; tropisetron, 7.3 hours; dolasetron, 7.5 hours).
In guinea-pig isolated ileum, RS 25259-198 antagonized contractile responses to 5-HT. The apparent functional affinity (pKB) was 6.7 ± 0.1. [2] In radioligand binding assays using [³H]-quipazine in membranes from NG-108-15 cells, RS 25259-198 exhibited a binding affinity (pKi) of 8.40 ± 0.07, with a Hill coefficient (nH) of 0.89 ± 0.08. [2] |
| ln Vivo |
Quantitative autoradiographic studies in rat brain indicated a differential distribution of 5-HT3receptor sites by [3H]-RS 25259-197. High densities of sites were seen in nuclear tractus solitaris and area postrema, a medium density in spinal trigeminal tract, ventral dentate gyrus and basal medial amygdala,and a low density of sites in hippocampal CAl, parietal cortex, medium raphe and cerebellum.7 In conclusion, the functional, binding and distribution studies undertaken with the radiolabelled and non-radiolabelled RS 25259-197 (S,S enantiomer) established the profile of a highly potent and selective5-HT3 receptor antagonist[2].
In a Phase III, randomized, double-blind study involving 563 adult cancer patients receiving moderately emetogenic chemotherapy, a single intravenous dose of palonosetron 0.25 mg was significantly superior to a single intravenous dose of ondansetron 32 mg in preventing acute (0–24 h), delayed (24–120 h), and overall (0–120 h) chemotherapy-induced nausea and vomiting (CINV). Complete response rates (no emesis and no rescue medication) were: Acute: 81.0% vs 68.6% (P<0.01); Delayed: 74.1% vs 55.1% (P<0.001); Overall: 69.3% vs 50.3% (P<0.001). [1] Complete control rates (no emesis, no rescue medication, and no more than mild nausea) were also significantly higher for palonosetron 0.25 mg compared to ondansetron during the delayed (66.7% vs 50.3%; P=0.001) and overall (63.0% vs 44.9%; P=0.001) intervals. [1] Time to treatment failure (first emetic episode or first use of rescue medication) was significantly longer following treatment with palonosetron 0.25 mg compared to ondansetron (P<0.001). The first quartile time to treatment failure was more than twice as long with palonosetron 0.25 mg (46.5 hours) than with ondansetron (19.5 hours). [1] Palonosetron 0.25 mg was consistently superior to ondansetron in the number of emetic episodes during acute, delayed, and overall intervals, the proportion of patients with no emetic episodes, and the proportion of nausea-free patients on study days 3–5. [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).
Guinea-pig ileum contractility assay: Segments (2 cm) of proximal ileum were suspended in Tyrode solution (containing methysergide to block 5-HT1/5-HT2 receptors and 5-methoxytryptamine to desensitize 5-HT1P receptors) under 1g resting tension at 37°C. Non-cumulative concentration-response curves to 5-HT (10 nM – 10 μM) were constructed in the absence and presence of the antagonist after a 60-minute equilibration period. The apparent affinity (pKB) was calculated from the concentration-ratio shift. [2] [³H]-quipazine binding assay: Membranes were prepared and incubated in a Tris-Krebs buffer at 25°C for 60 minutes. Saturation studies used eight concentrations of [³H]-quipazine (4 pM to 4 nM). Competition studies were conducted with 0.1 to 0.4 nM of radioligand and 10 concentrations of the unlabeled compound. Non-specific binding was defined with 0.1 μM (S)-zacopride. Reactions were terminated by vacuum filtration over GF/B filters pretreated with 0.3% polyethyleneimine, followed by washing with ice-cold 0.1 M NaCl. Bound radioactivity was determined by liquid scintillation spectrometry. Binding data were analyzed using a four-parameter logistic equation with Cheng-Prusoff correction. [2] |
| 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[2]
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). |
| ADME/Pharmacokinetics |
Palonosetron has a plasma elimination half-life of approximately 40 hours, which is significantly longer than other 5-HT3 receptor antagonists (e.g., ondansetron: approximately 4 hours; topirasetron: approximately 7.3 hours; dolasetron: approximately 7.5 hours; granisetron: approximately 8.9 hours). [1]
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| Toxicity/Toxicokinetics |
Palonosetron was well tolerated in the Phase III clinical trial. The most common treatment-related adverse event (adverse reaction) was headache, which was reported in 4.8% of patients receiving 0.25 mg palonosetron and in 5.3% of patients receiving 0.75 mg palonosetron (5.3% in the ondansetron group). [1] Other treatment-related adverse events with an incidence of more than 2% included constipation (1.6% in the 0.25 mg palonosetron group and 3.2% in the 0.75 mg palonosetron group) and dizziness (0.5% in the 0.25 mg palonosetron group and 3.2% in the ondansetron group). [1] No significant changes in laboratory parameters, vital signs or electrocardiogram (ECG) records were observed that were related to treatment. The mean change from baseline in the palonosetron 0.25 mg group and the palonosetron 0.75 mg group was 1 ms and 2 ms, respectively. [1]
Most adverse events were assessed to be related to the patient's underlying cancer or chemotherapy, rather than to the study drug. No major safety issues were identified. [1] |
| References | |
| Additional Infomation |
RS 25259-198 is one of the four enantiomers of the isoquinoline compound RS 25259-197. Its full chemical name is (3aR)-2-[(1R)-1-azabicyclo[2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1H-benzo[de]isoquinoline hydrochloride. [2] Of the four enantiomers tested, RS 25259-198 (R,R) showed the lowest apparent affinity (pKB = 6.7) for the 5-HT₃ receptor mediating isolated guinea pig ileum contraction, while the (S,S) enantiomer (pKB = 8.8) showed a lower affinity. [2]
RS 25259-198 is a highly selective 5-HT₃ receptor antagonist. Binding studies have shown that it has low affinity for 28 other neurotransmitter receptors and ion channels, including adrenergic receptors, muscarinic receptors, dopamine receptors, opioid receptors, and other 5-HT receptor subtypes (pKi < 6.0). [2] Palonosetron is a novel second-generation 5-HT3 receptor antagonist designed to improve the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV), where first-generation 5-HT3 antagonists have limited efficacy. [1] A single dose of palonosetron provides sustained antiemetic efficacy, which may be related to its high receptor binding affinity and long plasma half-life. [1] The doses chosen in the Phase III study (0.25 mg and 0.75 mg) were based on a previous Phase II dose-finding study that determined 0.25 mg (approximately 3.0 µg/kg) to be the lowest effective dose for preventing chemotherapy-induced nausea and vomiting (CINV) following highly emetogenic chemotherapy. [1] This study demonstrated that, for patients receiving moderately emetogenic chemotherapy, a single intravenous injection of 0.25 mg palonosetron provided superior and longer-lasting protection against CINV compared to ondansetron. [1] |
| Molecular Formula |
C19H24N2O.HCL
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|---|---|
| Molecular Weight |
332.87
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| Exact Mass |
332.17
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| Elemental Analysis |
C, 76.99; H, 8.16; N, 9.45; O, 5.40
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| CAS # |
135729-75-8
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| Related CAS # |
Palonosetron hydrochloride; 135729-62-3; Palonosetron; 135729-61-2
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| PubChem CID |
18651160
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| Appearance |
Solid
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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 |
1
|
| Hydrogen Bond Acceptor Count |
2
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
23
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| Complexity |
456
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| Defined Atom Stereocenter Count |
2
|
| SMILES |
O=C1N(C[C@]([H])(CCC2)C3=C2C=CC=C13)[C@H]4CN5CCC4CC5.[H]Cl
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| InChi Key |
OLDRWYVIKMSFFB-NBLXOJGSSA-N
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| InChi Code |
InChI=1S/C19H24N2O.ClH/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;1H/t15-,17-;/m0./s1
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| Chemical Name |
(3aR)-2-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-3a,4,5,6-tetrahydro-3H-benzo[de]isoquinolin-1-one;hydrochloride
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| Synonyms |
(R,R)-RS 25259, RS-25233-197; RS25233-198; RS 25259 197; RS 25233-197; (R,R)-RS25233-197; RS-25233-198; RS 25233-198; RS-25259-197; (R,R)-Palonosetron hydrochloride; US brand name: Aloxi and 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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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 | 3.0042 mL | 15.0209 mL | 30.0418 mL | |
| 5 mM | 0.6008 mL | 3.0042 mL | 6.0084 mL | |
| 10 mM | 0.3004 mL | 1.5021 mL | 3.0042 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05690802 | Recruiting | Drug: Palonosetron hydrochloride capsules |
Nausea and Vomiting | Xijing Hospital | May 16, 2022 | Not Applicable |
| NCT01370408 | Completed | Drug: Palonosetron Drug: ondansetron |
Chemotherapy-induced Nausea and Vomiting |
Northside Hospital, Inc. | February 2012 | Phase 2 |
| NCT03817970 | Recruiting | Drug: Palonosetron Drug: Ondansetron |
Nephrotoxicity | University of Colorado, Denver | November 15, 2019 | Phase 3 |
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