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Identification
NamePalonosetron
Accession NumberDB00377  (APRD00351)
TypeSmall Molecule
GroupsApproved, Investigational
Description

Palonosetron (INN, trade name Aloxi) is a 5-HT3 antagonist used in the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV). It is the most effective of the 5-HT3 antagonists in controlling delayed CINV nausea and vomiting that appear more than 24 hours after the first dose of a course of chemotherapy and is the only drug of its class approved for this use by the U.S. Food and Drug Administration. As of 2008, it is the most recent 5-HT3 antagonist to enter clinical use. [wikipedia]

Structure
Thumb
Synonyms
(3aS)-2-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-2,3,3a, 4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one
(3aS)-2,3,3a,4,5,6-hexahydro-2-[(3S)-3-quinuclidinyl]-1H-benz[de]isoquinolin-1-one
Palonosetron
Palonosétron
Palonosetrón
Palonosetronum
External Identifiers
  • 2-Qhbiqo
  • RS 25259
  • RS 25259-197
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Aloxiinjection.25 mg/5mLintravenousEisai Inc.2014-05-28Not applicableUs
Aloxicapsule0.5 mgoralEisai Limited2012-08-07Not applicableCanada
Aloxisolution0.25 mgintravenousEisai Limited2012-07-19Not applicableCanada
Aloxicapsule, gelatin coated.5 mg/1oralEisai Inc.2008-08-22Not applicableUs
Aloxiinjection.075 mg/1.5mLintravenousEisai Inc.2014-05-28Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
JioutingJiuyuan Gene Engineering
OnicitPfizer
PalnoxGlenmark
PaloxiKalbe
PalzenDr. Reddy's
ThemisetThemis Medicare
ZhiruoChia Tai Tianqing
Brand mixtures
NameLabellerIngredients
AkynzeoEisai Inc.
Salts
Name/CASStructureProperties
Palonosetron Hydrochloride
ThumbNot applicableDBSALT001057
Categories
UNII29WVV1OJ05
CAS number135729-56-5
WeightAverage: 296.414
Monoisotopic: 296.188863401
Chemical FormulaC19H24N2O
InChI KeyCPZBLNMUGSZIPR-NVXWUHKLSA-N
InChI
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
IUPAC Name
(5S)-3-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(12),9(13),10-trien-2-one
SMILES
[H][C@]12CCCC3=C1C(=CC=C3)C(=O)N(C2)[C@@H]1CN2CCC1CC2
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as isoquinolones and derivatives. These are aromatic polycyclic compounds containing a ketone bearing isoquinoline moiety.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassIsoquinolines and derivatives
Sub ClassIsoquinolones and derivatives
Direct ParentIsoquinolones and derivatives
Alternative Parents
Substituents
  • Isoquinolone
  • Tetrahydroisoquinoline
  • Tetralin
  • Quinuclidine
  • Piperidine
  • Benzenoid
  • Tertiary carboxylic acid amide
  • Tertiary aliphatic amine
  • Tertiary amine
  • Lactam
  • Carboxamide group
  • Amino acid or derivatives
  • Carboxylic acid derivative
  • Azacycle
  • Hydrocarbon derivative
  • Organic oxide
  • Organic oxygen compound
  • Amine
  • Organooxygen compound
  • Organonitrogen compound
  • Organic nitrogen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationFor the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy, as well as prevention of acute nausea and vomiting associated with highly emetogenic cancer chemotherapy. Also used for the prevention of postoperative nausea and vomiting for up to 24 hours post operation.
PharmacodynamicsPalonosetron is an antinauseant and antiemetic agent indicated for the prevention of nausea and vomiting associated with moderately-emetogenic cancer chemotherapy and for the prevention of postoperative nausea and vomiting. Palonosetron is a highly specific and selective serotonin 5-HT3 receptor antagonist that is pharmacologically related to other 5-HT3 receptor antagonists, but differs structurally. Palonosetron has a high affinity for 5-HT3 receptors, but has little to no affinity for other receptors. The serontonin 5-HT3 receptors are located on the nerve terminals of the vagus in the periphery, and centrally in the chemoreceptor trigger zone of the area postrema. It is suggested that chemotherapeutic agents release serotonin from the enterochromaffin cells of the small intestine by causing degenerative changes in the GI tract. The serotonin then stimulates the vagal and splanchnic nerve receptors that project to the medullary vomiting center, as well as the 5-HT3 receptors in the area postrema, thus initiating the vomiting reflex, causing nausea and vomiting.
Mechanism of actionPalonosetron is a selective serotonin 5-HT3 receptor antagonist. The antiemetic activity of the drug is brought about through the inhibition of 5-HT3 receptors present both centrally (medullary chemoreceptor zone) and peripherally (GI tract). This inhibition of 5-HT3 receptors in turn inhibits the visceral afferent stimulation of the vomiting center, likely indirectly at the level of the area postrema, as well as through direct inhibition of serotonin activity within the area postrema and the chemoreceptor trigger zone. Alternative mechanisms appear to be primarily responsible for delayed nausea and vomiting induced by emetogenic chemotherapy, since similar temporal relationships between between serotonin and emesis beyond the first day after a dose have not been established, and 5-HT3 receptor antagonists generally have not appeared to be effective alone in preventing or ameliorating delayed effects. It has been hypothesized that palonosetron's potency and long plasma half-life may contribute to its observed efficacy in preventing delayed nausea and vomiting caused by moderately emetogenic cancer chemotherapy.
Related Articles
AbsorptionLow oral bioavailability.
Volume of distribution
  • 8.3 ± 2.5 L/kg
Protein binding62%
Metabolism

Hepatic (50%), primarily CYP2D6-mediated, although CYP3A4 and CYP1A2 are also involved.

Route of eliminationAfter a single intravenous dose of 10 mcg/kg [14C]-palonosetron, approximately 80% of the dose was recovered within 144 hours in the urine
Half lifeApproximately 40 hours
Clearance
  • 160 +/- 35 mL/h/kg
ToxicityA single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9899
Blood Brain Barrier+0.9953
Caco-2 permeable+0.5986
P-glycoprotein substrateSubstrate0.679
P-glycoprotein inhibitor IInhibitor0.8643
P-glycoprotein inhibitor IINon-inhibitor0.6745
Renal organic cation transporterInhibitor0.5763
CYP450 2C9 substrateNon-substrate0.83
CYP450 2D6 substrateSubstrate0.7618
CYP450 3A4 substrateSubstrate0.6446
CYP450 1A2 substrateInhibitor0.6626
CYP450 2C9 inhibitorNon-inhibitor0.541
CYP450 2D6 inhibitorNon-inhibitor0.7502
CYP450 2C19 inhibitorInhibitor0.9367
CYP450 3A4 inhibitorInhibitor0.6002
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.7828
Ames testNon AMES toxic0.8664
CarcinogenicityNon-carcinogens0.9557
BiodegradationNot ready biodegradable0.9762
Rat acute toxicity2.7383 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.883
hERG inhibition (predictor II)Inhibitor0.6891
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Helsinn healthcare sa
Packagers
Dosage forms
FormRouteStrength
Capsuleoral
Capsuleoral0.5 mg
Capsule, gelatin coatedoral.5 mg/1
Injectionintravenous.075 mg/1.5mL
Injectionintravenous.25 mg/5mL
Solutionintravenous0.25 mg
Prices
Unit descriptionCostUnit
Aloxi 0.075 mg/1.5 ml vial52.8USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5202333 Yes1995-10-132015-10-13Us
US6297375 No2000-02-222020-02-22Us
US7947724 Yes2004-07-302024-07-30Us
US7947725 Yes2004-07-302024-07-30Us
US7960424 Yes2004-07-302024-07-30Us
US8518981 Yes2004-07-302024-07-30Us
US8598218 Yes2004-07-302024-07-30Us
US8598219 Yes2004-07-302024-07-30Us
US8623826 No2010-11-182030-11-18Us
US8729094 Yes2004-07-302024-07-30Us
US8951969 No2010-11-182030-11-18Us
US9066980 Yes2004-07-302024-07-30Us
US9125905 Yes2004-07-302024-07-30Us
US9173942 Yes2004-07-302024-07-30Us
US9186357 No2010-11-182030-11-18Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
logP2.7Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.464 mg/mLALOGPS
logP2.72ALOGPS
logP2.55ChemAxon
logS-2.8ALOGPS
pKa (Strongest Basic)7.97ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area23.55 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity88.52 m3·mol-1ChemAxon
Polarizability33.9 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Pierluigi Rossetto, Peter MacDonald, Ettore Bigatti, Gaia Banfi, Dario Tentorio, “Processes for preparing palonosetron salts.” U.S. Patent US20080200681, issued August 21, 2008.

US20080200681
General References
  1. De Leon A: Palonosetron (Aloxi): a second-generation 5-HT(3) receptor antagonist for chemotherapy-induced nausea and vomiting. Proc (Bayl Univ Med Cent). 2006 Oct;19(4):413-6. [PubMed:17106506 ]
  2. Stoltz R, Cyong JC, Shah A, Parisi S: Pharmacokinetic and safety evaluation of palonosetron, a 5-hydroxytryptamine-3 receptor antagonist, in U.S. and Japanese healthy subjects. J Clin Pharmacol. 2004 May;44(5):520-31. [PubMed:15102873 ]
  3. Rubenstein EB: Palonosetron: a unique 5-HT3 receptor antagonist indicated for the prevention of acute and delayed chemotherapy-induced nausea and vomiting. Clin Adv Hematol Oncol. 2004 May;2(5):284-9. [PubMed:16163194 ]
  4. Yang LP, Scott LJ: Palonosetron: in the prevention of nausea and vomiting. Drugs. 2009 Nov 12;69(16):2257-78. doi: 10.2165/11200980-000000000-00000. [PubMed:19852528 ]
  5. Siddiqui MA, Scott LJ: Palonosetron. Drugs. 2004;64(10):1125-32; discussion 1133-4. [PubMed:15139789 ]
  6. Eisenberg P, MacKintosh FR, Ritch P, Cornett PA, Macciocchi A: Efficacy, safety and pharmacokinetics of palonosetron in patients receiving highly emetogenic cisplatin-based chemotherapy: a dose-ranging clinical study. Ann Oncol. 2004 Feb;15(2):330-7. [PubMed:14760130 ]
  7. Stoltz R, Parisi S, Shah A, Macciocchi A: Pharmacokinetics, metabolism and excretion of intravenous [l4C]-palonosetron in healthy human volunteers. Biopharm Drug Dispos. 2004 Nov;25(8):329-37. [PubMed:15378559 ]
External Links
ATC CodesA04AA05A04AA55
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (185 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
ApomorphinePalonosetron may increase the hypotensive activities of Apomorphine.
BexaroteneThe serum concentration of Palonosetron can be decreased when it is combined with Bexarotene.
BudesonideThe serum concentration of Budesonide can be increased when it is combined with Palonosetron.
DexamethasoneThe serum concentration of Dexamethasone can be increased when it is combined with Palonosetron.
DoxorubicinThe serum concentration of Doxorubicin can be increased when it is combined with Palonosetron.
FlunisolideThe serum concentration of Flunisolide can be increased when it is combined with Palonosetron.
FluvoxaminePalonosetron may increase the serotonergic activities of Fluvoxamine.
PhenytoinThe serum concentration of Palonosetron can be decreased when it is combined with Phenytoin.
St. John's WortThe serum concentration of Palonosetron can be decreased when it is combined with St. John's Wort.
TapentadolPalonosetron may decrease the analgesic activities of Tapentadol.
TramadolPalonosetron may decrease the analgesic activities of Tramadol.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
General Function:
Voltage-gated potassium channel activity
Specific Function:
This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor is a ligand-gated ion channel, which when activated causes fast, depolarizing responses in neurons. It is a cation-specific, but otherwise relatively nonselective, ion channel.
Gene Name:
HTR3A
Uniprot ID:
P46098
Molecular Weight:
55279.835 Da
References
  1. Hesketh PJ: New treatment options for chemotherapy-induced nausea and vomiting. Support Care Cancer. 2004 Aug;12(8):550-4. Epub 2004 Jun 30. [PubMed:15232725 ]
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
  3. Grunberg SM, Koeller JM: Palonosetron: a unique 5-HT3-receptor antagonist for the prevention of chemotherapy-induced emesis. Expert Opin Pharmacother. 2003 Dec;4(12):2297-303. [PubMed:14640928 ]
  4. Rubenstein EB: Palonosetron: a unique 5-HT3 receptor antagonist indicated for the prevention of acute and delayed chemotherapy-induced nausea and vomiting. Clin Adv Hematol Oncol. 2004 May;2(5):284-9. [PubMed:16163194 ]
  5. Eisenberg P, Figueroa-Vadillo J, Zamora R, Charu V, Hajdenberg J, Cartmell A, Macciocchi A, Grunberg S: Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003 Dec 1;98(11):2473-82. [PubMed:14635083 ]
  6. Stoltz R, Cyong JC, Shah A, Parisi S: Pharmacokinetic and safety evaluation of palonosetron, a 5-hydroxytryptamine-3 receptor antagonist, in U.S. and Japanese healthy subjects. J Clin Pharmacol. 2004 May;44(5):520-31. [PubMed:15102873 ]
  7. De Leon A: Palonosetron (Aloxi): a second-generation 5-HT(3) receptor antagonist for chemotherapy-induced nausea and vomiting. Proc (Bayl Univ Med Cent). 2006 Oct;19(4):413-6. [PubMed:17106506 ]
  8. Yang LP, Scott LJ: Palonosetron: in the prevention of nausea and vomiting. Drugs. 2009 Nov 12;69(16):2257-78. doi: 10.2165/11200980-000000000-00000. [PubMed:19852528 ]
  9. Navari RM: Palonosetron: a second-generation 5-hydroxytryptamine receptor antagonist. Future Oncol. 2006 Oct;2(5):591-602. [PubMed:17026451 ]
  10. Gralla R, Lichinitser M, Van Der Vegt S, Sleeboom H, Mezger J, Peschel C, Tonini G, Labianca R, Macciocchi A, Aapro M: Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003 Oct;14(10):1570-7. [PubMed:14504060 ]
  11. Siddiqui MA, Scott LJ: Palonosetron. Drugs. 2004;64(10):1125-32; discussion 1133-4. [PubMed:15139789 ]
  12. Eisenberg P, MacKintosh FR, Ritch P, Cornett PA, Macciocchi A: Efficacy, safety and pharmacokinetics of palonosetron in patients receiving highly emetogenic cisplatin-based chemotherapy: a dose-ranging clinical study. Ann Oncol. 2004 Feb;15(2):330-7. [PubMed:14760130 ]
  13. Stoltz R, Parisi S, Shah A, Macciocchi A: Pharmacokinetics, metabolism and excretion of intravenous [l4C]-palonosetron in healthy human volunteers. Biopharm Drug Dispos. 2004 Nov;25(8):329-37. [PubMed:15378559 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Steroid hydroxylase activity
Specific Function:
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.
Gene Name:
CYP2D6
Uniprot ID:
P10635
Molecular Weight:
55768.94 Da
References
  1. Stoltz R, Parisi S, Shah A, Macciocchi A: Pharmacokinetics, metabolism and excretion of intravenous [l4C]-palonosetron in healthy human volunteers. Biopharm Drug Dispos. 2004 Nov;25(8):329-37. [PubMed:15378559 ]
  2. Stoltz R, Cyong JC, Shah A, Parisi S: Pharmacokinetic and safety evaluation of palonosetron, a 5-hydroxytryptamine-3 receptor antagonist, in U.S. and Japanese healthy subjects. J Clin Pharmacol. 2004 May;44(5):520-31. [PubMed:15102873 ]
  3. Janicki PK: Cytochrome P450 2D6 metabolism and 5-hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting. Med Sci Monit. 2005 Oct;11(10):RA322-8. Epub 2005 Sep 26. [PubMed:16192915 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. Stoltz R, Parisi S, Shah A, Macciocchi A: Pharmacokinetics, metabolism and excretion of intravenous [l4C]-palonosetron in healthy human volunteers. Biopharm Drug Dispos. 2004 Nov;25(8):329-37. [PubMed:15378559 ]
  2. Stoltz R, Cyong JC, Shah A, Parisi S: Pharmacokinetic and safety evaluation of palonosetron, a 5-hydroxytryptamine-3 receptor antagonist, in U.S. and Japanese healthy subjects. J Clin Pharmacol. 2004 May;44(5):520-31. [PubMed:15102873 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N...
Gene Name:
CYP1A2
Uniprot ID:
P05177
Molecular Weight:
58293.76 Da
References
  1. Stoltz R, Parisi S, Shah A, Macciocchi A: Pharmacokinetics, metabolism and excretion of intravenous [l4C]-palonosetron in healthy human volunteers. Biopharm Drug Dispos. 2004 Nov;25(8):329-37. [PubMed:15378559 ]
  2. Stoltz R, Cyong JC, Shah A, Parisi S: Pharmacokinetic and safety evaluation of palonosetron, a 5-hydroxytryptamine-3 receptor antagonist, in U.S. and Japanese healthy subjects. J Clin Pharmacol. 2004 May;44(5):520-31. [PubMed:15102873 ]
Comments
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Drug created on June 13, 2005 07:24 / Updated on June 27, 2016 03:07