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Identification
NameGranisetron
Accession NumberDB00889  (APRD01002)
Typesmall molecule
Groupsapproved, investigational
Description

A serotonin receptor (5HT-3 selective) antagonist that has been used as an antiemetic and antinauseant for cancer chemotherapy patients. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
GranisetronumLatinINN
Salts
Name/CAS Structure Properties
Granisetron Hydrochloride
Thumb
  • InChI Key: QYZRTBKYBJRGJB-UHFFFAOYNA-N
  • Monoisotopic Mass: 348.171689149
  • Average Mass: 348.87
DBSALT000485
Brand names
NameCompany
GranisolNot Available
KytrilNot Available
SancusoNot Available
Brand mixturesNot Available
Categories
CAS number109889-09-0
WeightAverage: 312.4094
Monoisotopic: 312.19501141
Chemical FormulaC18H24N4O
InChI KeyMFWNKCLOYSRHCJ-UHFFFAOYSA-N
InChI
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)
IUPAC Name
1-methyl-N-{9-methyl-9-azabicyclo[3.3.1]nonan-3-yl}-1H-indazole-3-carboxamide
SMILES
CN1N=C(C(=O)NC2CC3CCCC(C2)N3C)C2=CC=CC=C12
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassBenzopyrazoles
SubclassIndazoles
Direct parentIndazoles
Alternative parentsAminopiperidines; Benzene and Substituted Derivatives; Pyrazoles; Tertiary Amines; Secondary Carboxylic Acid Amides; Carboxylic Acids; Enolates; Polyamines
Substituents4-aminopiperidine; piperidine; benzene; pyrazole; azole; tertiary amine; secondary carboxylic acid amide; carboxamide group; carboxylic acid derivative; enolate; polyamine; carboxylic acid; amine; organonitrogen compound
Classification descriptionThis compound belongs to the indazoles. These are compounds containing an indazole, which is structurally characterized by a pyrazole fused to a benzene.
Pharmacology
IndicationFor the prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer therapy (including high dose cisplatin), postoperation, and radiation (including total body irradiation and daily fractionated abdominal radiation).
PharmacodynamicsGranisetron is a selective inhibitor of type 3 serotonergic (5-HT3) receptors. Granisetron has little or no affinity for other serotonin receptors, including 5-HT 1 , 5-HT 1A , 5-HT 1B/C , or 5-HT 2 ; for alpha 1 -, alpha 2 -, or beta-adrenoreceptors; for dopamine D 2 receptors; for histamine H 1 receptors; for benzodiazepine receptors; for picrotoxin receptors; or for opioid receptors. In most human studies, granisetron has had little effect on blood pressure, heart rate, or electrocardiogram (ECG). The drug is structurally and pharmacologically related to ondansetron, another selective inhibitor of 5-HT3 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. The temporal relationship between the emetogenic action of emetogenic drugs and the release of serotonin, as well as the efficacy of antiemetic agents suggest 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 actionGranisetron is a potent, selective antagonist of 5-HT3 receptors. 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.
AbsorptionAbsorption of is rapid and complete, though oral bioavailability is reduced to about 60% as a result of first pass metabolism.
Volume of distributionNot Available
Protein binding65%
Metabolism

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.

SubstrateEnzymesProduct
Granisetron
9'-desmethylgranisetronDetails
Granisetron
7-hydroxygranisetronDetails
Route of eliminationThe remainder of the dose is excreted as metabolites, 48% in the urine and 38% in the feces.
Half life4-6 hours in healthy patients, 9-12 hours in cancer patients
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]
ToxicityLD50>2000 mg/kg (rat, oral)
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9947
Blood Brain Barrier + 0.9515
Caco-2 permeable + 0.5231
P-glycoprotein substrate Substrate 0.5473
P-glycoprotein inhibitor I Inhibitor 0.6287
P-glycoprotein inhibitor II Inhibitor 0.7243
Renal organic cation transporter Non-inhibitor 0.5895
CYP450 2C9 substrate Non-substrate 0.7898
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Substrate 0.6978
CYP450 1A2 substrate Non-inhibitor 0.8546
CYP450 2C9 substrate Non-inhibitor 0.9019
CYP450 2D6 substrate Non-inhibitor 0.8841
CYP450 2C19 substrate Non-inhibitor 0.9073
CYP450 3A4 substrate Non-inhibitor 0.8355
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.6016
Ames test Non AMES toxic 0.5878
Carcinogenicity Non-carcinogens 0.8464
Biodegradation Not ready biodegradable 0.9868
Rat acute toxicity 2.3943 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9083
hERG inhibition (predictor II) Inhibitor 0.5458
Pharmacoeconomics
Manufacturers
  • Strakan international ltd
  • Akorn inc
  • App pharmaceuticals llc
  • Baxter healthcare corp anesthesia and critical care
  • Bedford laboratories
  • Claris lifesciences ltd
  • Dr reddys laboratories inc
  • Ebewe pharma
  • Sagent strides llc
  • Sandoz canada inc
  • Teva parenteral medicines inc
  • Watson laboratories inc
  • Wockhardt usa inc
  • App pharmaceuticals
  • Hikma farmaceutica (portugal) sa
  • Hoffmann la roche inc
  • Cypress pharmaceutical inc
  • Apotex inc
  • Barr laboratories inc
  • Cipla ltd
  • Corepharma llc
  • Dr reddys laboratories ltd
  • Mylan pharmaceuticals inc
  • Natco pharma ltd
  • Orchid healthcare
  • Roxane laboratories inc
  • Taro pharmaceuticals usa inc
  • Teva pharmaceuticals usa
Packagers
Dosage forms
FormRouteStrength
LiquidIntravenous
TabletOral
Prices
Unit descriptionCostUnit
Sancuso 3.1 mg/24 hr patch372.0USDpatch
Kytril 2 1 mg tablet Box131.98USDbox
Kytril 1 mg tablet62.94USDtablet
Granisetron hcl 1 mg tablet60.19USDtablet
Granisetron hcl 4 mg/4 ml vial24.0USDml
Kytril 1 mg Tablet20.27USDtablet
Apo-Granisetron 1 mg Tablet14.14USDtablet
Kytril 0.1 mg/ml vial11.54USDml
Granisetron hcl 0.1 mg/ml vial7.2USDml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States76082822004-10-222024-10-22
United States59523401996-09-142016-09-14
Canada21583542004-07-132014-03-15
Canada21007772003-08-192012-01-16
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point219 °C (HCl salt)Not Available
logP2.6Not Available
Predicted Properties
PropertyValueSource
water solubility4.34e-01 g/lALOGPS
logP2.64ALOGPS
logP1.88ChemAxon
logS-2.9ALOGPS
pKa (strongest acidic)14.75ChemAxon
pKa (strongest basic)9ChemAxon
physiological charge1ChemAxon
hydrogen acceptor count3ChemAxon
hydrogen donor count1ChemAxon
polar surface area50.16ChemAxon
rotatable bond count2ChemAxon
refractivity101.83ChemAxon
polarizability35.39ChemAxon
number of rings4ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Neal Ward, David Alan Jones, Victor Witold Jacewicz, “Process for the preparation of granisetron.” U.S. Patent US6268498, issued April, 1986.

US6268498
General Reference
  1. Link
  2. Gan TJ: Selective serotonin 5-HT3 receptor antagonists for postoperative nausea and vomiting: are they all the same? CNS Drugs. 2005;19(3):225-38. Pubmed
  3. Tan M: Granisetron: new insights into its use for the treatment of chemotherapy-induced nausea and vomiting. Expert Opin Pharmacother. 2003 Sep;4(9):1563-71. Pubmed
  4. Feyer P, Seegenschmiedt MH, Steingraeber M: Granisetron in the control of radiotherapy-induced nausea and vomiting: a comparison with other antiemetic therapies. Support Care Cancer. 2005 Sep;13(9):671-8. Epub 2005 Jul 26. Pubmed
External Links
ResourceLink
KEGG DrugD04370
KEGG CompoundC07023
PubChem Compound3510
PubChem Substance46505137
ChemSpider3390
BindingDB50000483
Therapeutic Targets DatabaseDAP000295
PharmGKBPA449809
IUPHAR2300
Guide to Pharmacology2300
Drug Product Database2088371
RxListhttp://www.rxlist.com/cgi/generic/granisetron.htm
Drugs.comhttp://www.drugs.com/cdi/granisetron.html
WikipediaGranisetron
ATC CodesA04AA02
AHFS Codes
  • 56:22.20
PDB EntriesNot Available
FDA labelshow(77.3 KB)
MSDSshow(51.7 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

1. 5-hydroxytryptamine receptor 3A

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
5-hydroxytryptamine receptor 3A P46098 Details

References:

  1. Hillsley K, Grundy D: Plasticity in the mesenteric afferent response to cisplatin following vagotomy in the rat. J Auton Nerv Syst. 1999 May 28;76(2-3):93-8. Pubmed
  2. Turvill JL, Connor P, Farthing MJ: The inhibition of cholera toxin-induced 5-HT release by the 5-HT receptor antagonist, granisetron, in the rat. Br J Pharmacol. 2000 Jul;130(5):1031-6. Pubmed
  3. Cappelli A, Anzini M, Vomero S, Mennuni L, Makovec F, Doucet E, Hamon M, Menziani MC, De Benedetti PG, Giorgi G, Ghelardini C, Collina S: Novel potent 5-HT receptor ligands based on the pyrrolidone structure: synthesis, biological evaluation, and computational rationalization of the ligand-receptor interaction modalities. Bioorg Med Chem. 2002 Mar;10(3):779-801. Pubmed
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  5. Gan TJ: Selective serotonin 5-HT3 receptor antagonists for postoperative nausea and vomiting: are they all the same? CNS Drugs. 2005;19(3):225-38. Pubmed
  6. Tan M: Granisetron: new insights into its use for the treatment of chemotherapy-induced nausea and vomiting. Expert Opin Pharmacother. 2003 Sep;4(9):1563-71. Pubmed
  7. Ho KY, Gan TJ: Pharmacology, pharmacogenetics, and clinical efficacy of 5-hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting. Curr Opin Anaesthesiol. 2006 Dec;19(6):606-11. Pubmed
  8. Abdelsayed GG: Management of radiation-induced nausea and vomiting. Exp Hematol. 2007 Apr;35(4 Suppl 1):34-6. Pubmed
  9. Feyer P, Seegenschmiedt MH, Steingraeber M: Granisetron in the control of radiotherapy-induced nausea and vomiting: a comparison with other antiemetic therapies. Support Care Cancer. 2005 Sep;13(9):671-8. Epub 2005 Jul 26. Pubmed

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Tan M: Granisetron: new insights into its use for the treatment of chemotherapy-induced nausea and vomiting. Expert Opin Pharmacother. 2003 Sep;4(9):1563-71. Pubmed
  2. 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
  3. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 1A1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A1 P04798 Details

References:

  1. Nakamura H, Ariyoshi N, Okada K, Nakasa H, Nakazawa K, Kitada M: CYP1A1 is a major enzyme responsible for the metabolism of granisetron in human liver microsomes. Curr Drug Metab. 2005 Oct;6(5):469-80. Pubmed
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

3. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor inducer

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

4. Cytochrome P450 3A5

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A5 P20815 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:12