Identification

Name
Dolasetron
Accession Number
DB00757  (APRD00518)
Type
Small Molecule
Groups
Approved, Investigational
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
  • Dolasetronum
External IDs
MDL 73147 EF
Product Ingredients
IngredientUNIICASInChI Key
Dolasetron MesylateU3C8E5BWKR878143-33-0QTFFGPOXNNGTGZ-UXSNJBPXSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AnzemetTablet, film coated100 mg/1OralPhysicians Total Care, Inc.1997-09-112010-06-30Us
AnzemetTablet100 mgOralSanofi Aventis1997-08-262014-04-21Canada
AnzemetTablet, film coated100 mg/1OralAvera McKennan Hospital2016-07-26Not applicableUs
AnzemetTablet, film coated100 mg/1OralSanofi Aventis1997-09-11Not applicableUs
AnzemetInjection100 mg/5mLIntravenousSanofi Aventis1997-09-11Not applicableUs
AnzemetTablet50 mgOralSanofi Aventis1997-08-26Not applicableCanada
AnzemetTablet, film coated100 mg/1OralValidus Pharmaceuticals1997-09-11Not applicableUs
AnzemetTablet, film coated50 mg/1OralSanofi Aventis1997-09-11Not applicableUs
AnzemetInjection12.5 mg/0.625mLIntravenousSanofi Aventis1997-09-11Not applicableUs
AnzemetTablet, film coated50 mg/1OralValidus Pharmaceuticals1997-09-11Not applicableUs
International/Other Brands
Anemet (Sanofi-Aventis) / Zamanon (Sanofi-Aventis)
Categories
UNII
82WI2L7Q6E
CAS number
115956-12-2
Weight
Average: 324.38
Monoisotopic: 324.147392512
Chemical Formula
C19H20N2O3
InChI Key
UKTAZPQNNNJVKR-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
(1s,3R,5r,7S)-10-oxo-8-azatricyclo[5.3.1.0³,⁸]undecan-5-yl 1H-indole-3-carboxylate
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

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.

Associated Conditions
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.

TargetActionsOrganism
A5-hydroxytryptamine receptor 3A
antagonist
Human
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
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbirateroneThe serum concentration of Dolasetron can be increased when it is combined with Abiraterone.
Acetyl sulfisoxazoleThe metabolism of Dolasetron can be decreased when combined with Acetyl sulfisoxazole.
AlbendazoleThe metabolism of Dolasetron can be decreased when combined with Albendazole.
AlclometasoneThe metabolism of Alclometasone can be decreased when combined with Dolasetron.
AlfuzosinThe risk or severity of QTc prolongation can be increased when Alfuzosin is combined with Dolasetron.
AlimemazineThe risk or severity of QTc prolongation can be increased when Alimemazine is combined with Dolasetron.
AlmotriptanDolasetron may increase the serotonergic activities of Almotriptan.
AlprazolamThe metabolism of Alprazolam can be decreased when combined with Dolasetron.
AmantadineAmantadine may increase the QTc-prolonging activities of Dolasetron.
AmcinonideThe metabolism of Amcinonide can be decreased when combined with Dolasetron.
Food Interactions
  • Take without regard to meals.

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
KEGG Compound
C07866
PubChem Compound
3033818
PubChem Substance
46505209
ChemSpider
30845229
BindingDB
50451546
ChEMBL
CHEMBL2368925
Therapeutic Targets Database
DAP000368
PharmGKB
PA449390
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Dolasetron
ATC Codes
A04AA04 — Dolasetron
AHFS Codes
  • 56:22.20 — 5-HT3 Receptor Antagonists
FDA label
Download (93.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentProphylaxis against postoperative nausea and vomiting / Prophylaxis of acute chemotherapy induced nausea and vomiting1
2CompletedSupportive CareNausea and Vomiting / Unspecified Adult Solid Tumor, Protocol Specific1
3CompletedSupportive CareNausea and Vomiting / Unspecified Adult Solid Tumor, Protocol Specific1
3CompletedTreatmentFibromyalgia1
Not AvailableCompletedPreventionProphylaxis against postoperative nausea and vomiting1
Not AvailableTerminatedSupportive CareMalignant Digestive System Neoplasm / Nausea and Vomiting1

Pharmacoeconomics

Manufacturers
  • Sanofi aventis us llc
Packagers
  • Cardinal Health
  • Gruppo Lepetit SPA
  • Hospira Inc.
  • Merrell Pharmaceuticals Inc.
  • Patheon Inc.
  • Physicians Total Care Inc.
  • Sanofi-Aventis Inc.
Dosage forms
FormRouteStrength
InjectionIntravenous100 mg/5mL
InjectionIntravenous12.5 mg/0.625mL
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)
US4906755No1994-07-022011-07-02Us
CA1329203No1994-05-032011-05-03Canada

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)278 °CNot Available
water solubilityFreely soluble in waterNot Available
logP2.1Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.261 mg/mLALOGPS
logP2.41ALOGPS
logP2.33ChemAxon
logS-3.1ALOGPS
pKa (Strongest Acidic)12.18ChemAxon
pKa (Strongest Basic)5.68ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area62.4 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity89.34 m3·mol-1ChemAxon
Polarizability35.02 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as indolecarboxylic acids and derivatives. These are compounds containing a carboxylic acid group (or a derivative thereof) linked to an indole.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Indoles and derivatives
Sub Class
Indolecarboxylic acids and derivatives
Direct Parent
Indolecarboxylic acids and derivatives
Alternative Parents
Quinolizidines / Indoles / Quinuclidones / Pyrrole carboxylic acids and derivatives / Piperidinones / Benzenoids / Substituted pyrroles / Vinylogous amides / Heteroaromatic compounds / Ketones
show 8 more
Substituents
Indolecarboxylic acid derivative / Quinolizidine / Indole / Quinuclidone / Pyrrole-3-carboxylic acid or derivatives / Quinuclidine / Piperidinone / Piperidine / Substituted pyrrole / Benzenoid
show 21 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not 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-gate...
Gene Name
HTR3A
Uniprot ID
P46098
Uniprot Name
5-hydroxytryptamine receptor 3A
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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
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...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
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 un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
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]

Drug created on June 13, 2005 07:24 / Updated on September 23, 2018 19:37