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Identification
Name Dolasetron
Accession Number DB00757 (APRD00518)
Type small molecule
Groups approved
Description

Dolasetron 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. Dolasetron is a highly specific and selective serotonin 5-HT3 receptor antagonist. This drug has not shown to have activity at other known serotonin receptors, and has low affinity for dopamine receptors.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms Not Available
Synonyms Not Available
Salts Not Available
Brand names
Name Company
Anzemet
Dolasetronum [INN-Latin]
Dolasteron
Brand mixtures Not Available
Categories
  • Antiemetics
  • Serotonin Antagonists
CAS number 115956-12-2
Weight Average: 324.3737
Monoisotopic: 324.147392516
Chemical Formula C19H20N2O3
InChI Key InChIKey=UKTAZPQNNNJVKR-DBBXXEFVSA-N
InChI
InChI=1S/C19H20N2O3/c22-18-10-21-12-5-11(18)6-13(21)8-14(7-12)24-19(23)16-9-20-17-4-2-1-3-15(16)17/h1-4,9,11-14,20H,5-8,10H2/t11?,12-,13?,14?/m1/s1
Plain Text
IUPAC Name
(3R)-10-oxo-8-azatricyclo[5.3.1.0^{3,8}]undecan-5-yl 1H-indole-3-carboxylate
SMILES
O=C(OC1CC2CC3C[C@H](C1)N2CC3=O)C1=CNC2=CC=CC=C12
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Indoles and Indole Derivatives
  • Quinolizines
  • (Iso)quinolines and Derivatives
  • Alkaloids and Alkaloid Derivatives
Substructures
  • Carboxylic Acids and Derivatives
  • Acetates
  • Indoles and Indole Derivatives
  • Amino Ketones
  • Pyrroles
  • Ethers
  • Benzene and Derivatives
  • Aliphatic and Aryl Amines
  • Quinolizines
  • Heterocyclic compounds
  • Aromatic compounds
  • (Iso)quinolines and Derivatives
  • Alkaloids and Alkaloid Derivatives
  • Cyclooctane and Derivatives
  • Piperidines
  • Ketones
Pharmacology
Indication For the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy, including initial and repeat courses of chemotherapy. Also used for the prevention of postoperative nausea and vomiting. This drug can be used intravenously for the treatment of postoperative nausea and vomiting.
Pharmacodynamics Dolasetron is a highly specific and selective serotonin 5-HT3 receptor antagonist, not shown to have activity at other known serotonin receptors and with low affinity for dopamine receptors. It is structurally and pharmacologically related to other 5-HT3 receptor agonists. 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 action Dolasetron is a selective serotonin 5-HT3 receptor antagonist. In vivo, the drug is rapidly converted into its major active metabolite, hydrodolasetron, which seems to be largely responsible for the drug's pharmacological activity. 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.
Absorption Orally-administered dolasetron is well absorbed
Volume of distribution
  • 5.8 L/kg [adults]
Protein binding 69-77%
Metabolism Hepatic
Route of elimination Hydrodolasetron is eliminated by multiple routes, including renal excretion and, after metabolism, mainly glucuronidation, and hydroxylation.
Half life 8.1 hours
Clearance
  • Apparent cl=9.4 mL/min/kg [Healthy volunteers with IV treatment dose up to 5 mg/kg]
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Sanofi aventis us llc
Packagers
Dosage forms
Form Route Strength
Solution Intravenous
Tablet Oral
Prices
Unit description Cost Unit
Anzemet 100 mg tablet 77.77 USD tablet
Anzemet 50 mg tablet 58.67 USD tablet
Anzemet 100 mg Tablet 32.16 USD tablet
Anzemet 12.5 mg carpuject 18.74 USD syringe
Anzemet 20 mg/ml 2.66 USD ml
Patents
Country Patent Number Approved Expires (estimated)
United States 4906755 1994-07-02 2011-07-02
Canada 1329203 1994-05-03 2011-05-03
Properties
State solid
Melting point 278 oC
Experimental Properties
Property Value Source
water solubility Freely soluble in water PhysProp
logP 2.1 PhysProp
Predicted Properties
Property Value Source
water solubility 2.61e-01 g/l ALOGPS
logP 2.41 ALOGPS
logP 2.33 ChemAxon Molconvert
logS -3.1 ALOGPS
pKa 18.25 ChemAxon Molconvert
hydrogen acceptor count 3 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 62.4 ChemAxon Molconvert
rotatable bond count 3 ChemAxon Molconvert
refractivity 89.34 ChemAxon Molconvert
polarizability 33.69 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Balfour JA, Goa KL: Dolasetron. A review of its pharmacology and therapeutic potential in the management of nausea and vomiting induced by chemotherapy, radiotherapy or surgery. Drugs. 1997 Aug;54(2):273-98. Pubmed
  2. Gregory RE, Ettinger DS: 5-HT3 receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting. A comparison of their pharmacology and clinical efficacy. Drugs. 1998 Feb;55(2):173-89. Pubmed
  3. 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
External Links
Resource Link
KEGG Compound C07866 Link_out
PubChem Compound 60654 Link_out
PubChem Substance 46505209 Link_out
ChemSpider 54666 Link_out
Therapeutic Targets Database DAP000368 Link_out
PharmGKB PA449390 Link_out
Drug Product Database 2231380 Link_out
RxList http://www.rxlist.com/cgi/generic2/dolaset.htm Link_out
Drugs.com http://www.drugs.com/cdi/dolasetron.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Dolasetron Link_out
ATC Codes
  • A04AA04
AHFS Codes
  • 56:22.20
PDB Entries Not Available
FDA label show (93.3 KB)
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Artemether Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Tacrolimus Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Thiothixene May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.
Toremifene Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.
Trimipramine Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Voriconazole Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Vorinostat Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Ziprasidone Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.
Zuclopenthixol Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Food Interactions
  • Take without regard to meals.
Targets

1. 5-hydroxytryptamine 3 receptor

Pharmacological action: yes
Actions: antagonist

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

Organism class: human
UniProt ID: P46098 Link_out
Gene: HTR3A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Conroy T, Cappelaere P, Fabbro M, Fauser AA, Splinter TA, Spielmann M, Schneider M, Chevallier B, Goupil A, Chauvergne J, et al.: Acute antiemetic efficacy and safety of dolasetron mesylate, a 5-HT3 antagonist, in cancer patients treated with cisplatin. European Dolasetron Study Group. Am J Clin Oncol. 1994 Apr;17(2):97-102. Pubmed
  3. Reith MK, Sproles GD, Cheng LK: Human metabolism of dolasetron mesylate, a 5-HT3 receptor antagonist. Drug Metab Dispos. 1995 Aug;23(8):806-12. Pubmed
  4. 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
  5. Monaca-Charley C, Stojkovic T, Duhamel A, De Seze J, Ferriby D, Vermersch P: Double-blind crossover study with dolasetron mesilate, a 5-HT3 receptor antagonist in cerebellar syndrome secondary to multiple sclerosis. J Neurol. 2003 Oct;250(10):1190-4. Pubmed
  6. Boeijinga PH, Galvan M, Baron BM, Dudley MW, Siegel BW, Slone AL: Characterization of the novel 5-HT3 antagonists MDL 73147EF (dolasetron mesilate) and MDL 74156 in NG108-15 neuroblastoma x glioma cells. Eur J Pharmacol. 1992 Aug 14;219(1):9-13. Pubmed
  7. Balfour JA, Goa KL: Dolasetron. A review of its pharmacology and therapeutic potential in the management of nausea and vomiting induced by chemotherapy, radiotherapy or surgery. Drugs. 1997 Aug;54(2):273-98. Pubmed
  8. Hui YF, Ignoffo RJ: Dolasetron. A new 5-hydroxytryptamine3 receptor antagonist. Cancer Pract. 1997 Sep-Oct;5(5):324-8. Pubmed
  9. Gregory RE, Ettinger DS: 5-HT3 receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting. A comparison of their pharmacology and clinical efficacy. Drugs. 1998 Feb;55(2):173-89. Pubmed
  10. 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
Enzymes

1. Cytochrome P450 3A4

Actions: substrate

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 xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Sanwald P, David M, Dow J: Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of dolasetron. Comparison with other indole-containing 5-HT3 antagonists. Drug Metab Dispos. 1996 May;24(5):602-9. Pubmed

2. Cytochrome P450 2D6

Actions: substrate

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

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. 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
  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. Sanwald P, David M, Dow J: Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of dolasetron. Comparison with other indole-containing 5-HT3 antagonists. Drug Metab Dispos. 1996 May;24(5):602-9. Pubmed

3. Cytochrome P450 2C9

Actions: substrate

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. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Comments
Drug created on June 13, 2005 07:24 / Updated on February 14, 2012 11:43