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Identification
NameDolasetron
Accession NumberDB00757  (APRD00518)
TypeSmall Molecule
GroupsApproved
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 is not shown to have activity at other known serotonin receptors, and has low affinity for dopamine receptors.

Structure
Thumb
Synonyms
Dolasetron
Dolasétron
Dolasetron
Dolasetronum
External Identifiers
  • MDL 73147 EF
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Anzemettablet, film coated50 mg/1oralSanofi Aventis U.S. Llc1997-09-11Not applicableUs
Anzemettablet100 mgoralSanofi Aventis Canada Inc1997-08-262014-04-21Canada
Anzemettablet50 mgoralSanofi Aventis Canada Inc1997-08-262010-01-01Canada
Anzemetinjection500 mg/25mLintravenousSanofi Aventis U.S. Llc1997-09-11Not applicableUs
Anzemetinjection12.5 mg/.625mLintravenousSanofi Aventis U.S. Llc1997-09-11Not applicableUs
Anzemetinjection100 mg/5mLintravenousSanofi Aventis U.S. Llc1997-09-11Not applicableUs
Anzemettablet, film coated100 mg/1oralSanofi Aventis U.S. Llc1997-09-11Not applicableUs
Anzemet Injection 20 mg/mlsolution20 mgintravenousSanofi Aventis Canada Inc1997-09-022011-08-15Canada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
AnemetSanofi-Aventis
ZamanonSanofi-Aventis
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Dolasetron Mesylate
ThumbNot applicableDBSALT000959
Categories
UNII82WI2L7Q6E
CAS number115956-12-2
WeightAverage: 324.38
Monoisotopic: 324.147392512
Chemical FormulaC19H20N2O3
InChI KeyUKTAZPQNNNJVKR-KJGYPYNMSA-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+
IUPAC Name
SMILES
[H][C@@]1(C[C@@]2([H])C[C@]3([H])C[C@@]([H])(C1)N2CC3=O)OC(=O)C1=CNC2=C1C=CC=C2
Taxonomy
ClassificationNot classified
Pharmacology
IndicationFor 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.
PharmacodynamicsDolasetron 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 actionDolasetron 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.
Related Articles
AbsorptionOrally-administered dolasetron is well absorbed
Volume of distribution
  • 5.8 L/kg [adults]
Protein binding69-77%
Metabolism

Hepatic

Route of eliminationHydrodolasetron is eliminated by multiple routes, including renal excretion and, after metabolism, mainly glucuronidation, and hydroxylation.
Half life8.1 hours
Clearance
  • Apparent cl=9.4 mL/min/kg [Healthy volunteers with IV treatment dose up to 5 mg/kg]
ToxicityNot Available
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+0.9956
Blood Brain Barrier+0.9403
Caco-2 permeable+0.5119
P-glycoprotein substrateNon-substrate0.5833
P-glycoprotein inhibitor IInhibitor0.5344
P-glycoprotein inhibitor IINon-inhibitor0.5225
Renal organic cation transporterInhibitor0.5
CYP450 2C9 substrateNon-substrate0.8569
CYP450 2D6 substrateSubstrate0.8919
CYP450 3A4 substrateNon-substrate0.5387
CYP450 1A2 substrateInhibitor0.5293
CYP450 2C9 inhibitorNon-inhibitor0.6846
CYP450 2D6 inhibitorNon-inhibitor0.9093
CYP450 2C19 inhibitorNon-inhibitor0.7741
CYP450 3A4 inhibitorNon-inhibitor0.8272
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5698
Ames testNon AMES toxic0.6931
CarcinogenicityNon-carcinogens0.9407
BiodegradationNot ready biodegradable0.9963
Rat acute toxicity2.5853 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8902
hERG inhibition (predictor II)Non-inhibitor0.7459
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Sanofi aventis us llc
Packagers
Dosage forms
FormRouteStrength
Injectionintravenous100 mg/5mL
Injectionintravenous12.5 mg/.625mL
Injectionintravenous500 mg/25mL
Tabletoral100 mg
Tabletoral50 mg
Tablet, film coatedoral100 mg/1
Tablet, film coatedoral50 mg/1
Solutionintravenous20 mg
Prices
Unit descriptionCostUnit
Anzemet 100 mg tablet77.77USD tablet
Anzemet 50 mg tablet58.67USD tablet
Anzemet 100 mg Tablet32.16USD tablet
Anzemet 12.5 mg carpuject18.74USD syringe
Anzemet 20 mg/ml2.66USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA1329203 No1994-05-032011-05-03Canada
US4906755 No1994-07-022011-07-02Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point278 °CNot Available
water solubilityFreely soluble in waterNot Available
logP2.1Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.261 mg/mLALOGPS
logP2.41ALOGPS
logS-3.1ALOGPS
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Janos Hajko, Tivadar Tamas, Adrienne Kovacsne-Mezei, Erika Molnarne, Csaba Peto, Csaba Szabo, “Production of dolasetron.” U.S. Patent US20070203219, issued August 30, 2007.

US20070203219
General References
  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:9257083 ]
  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:9506240 ]
  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:15740177 ]
External Links
ATC CodesA04AA04
AHFS Codes
  • 56:22.20
PDB EntriesNot Available
FDA labelDownload (93.3 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
ApomorphineDolasetron may increase the hypotensive activities of Apomorphine.
AripiprazoleThe serum concentration of Aripiprazole can be increased when it is combined with Dolasetron.
CitalopramDolasetron may increase the QTc-prolonging activities of Citalopram.
DofetilideDolasetron may increase the QTc-prolonging activities of Dofetilide.
FluvoxamineDolasetron may increase the serotonergic activities of Fluvoxamine.
GoserelinGoserelin may increase the QTc-prolonging activities of Dolasetron.
IvabradineIvabradine may increase the QTc-prolonging activities of Dolasetron.
LeuprolideLeuprolide may increase the QTc-prolonging activities of Dolasetron.
MequitazineDolasetron may increase the arrhythmogenic activities of Mequitazine.
MifepristoneMifepristone may increase the QTc-prolonging activities of Dolasetron.
OctreotideOctreotide may increase the QTc-prolonging activities of Dolasetron.
PanobinostatDolasetron may increase the arrhythmogenic activities of Panobinostat.
TapentadolDolasetron may decrease the analgesic activities of Tapentadol.
TramadolDolasetron may decrease the analgesic activities of Tramadol.
Food Interactions
  • Take without regard to meals.

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. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
  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:8141114 ]
  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:7493546 ]
  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:14635083 ]
  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:14586600 ]
  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:1397053 ]
  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:9257083 ]
  8. Hui YF, Ignoffo RJ: Dolasetron. A new 5-hydroxytryptamine3 receptor antagonist. Cancer Pract. 1997 Sep-Oct;5(5):324-8. [PubMed:9341357 ]
  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:9506240 ]
  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:15740177 ]

Enzymes

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. 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:8723743 ]
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. 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 ]
  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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
  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:8723743 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Steroid 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 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, phenyto...
Gene Name:
CYP2C9
Uniprot ID:
P11712
Molecular Weight:
55627.365 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
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Drug created on June 13, 2005 07:24 / Updated on May 09, 2016 16:43