DOLASETRON

Details

Stereochemistry	ACHIRAL
Molecular Formula	C19H20N2O3
Molecular Weight	324.3737
Optical Activity	NONE
Defined Stereocenters	4 / 4
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[H][C@@]12C[C@H](C[C@H]3C[C@@H](C1)C(=O)CN23)OC(=O)C4=CNC5=C4C=CC=C5

InChI

InChIKey=UKTAZPQNNNJVKR-YXSUXZIUSA-N

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-

HIDE SMILES / InChI

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020623s008lbl.pdf | https://www.ncbi.nlm.nih.gov/pubmed/21036635

Dolasetron is an antinauseant and antiemetic agent, which is approved as a mesylate salt under the brand name anzement for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy, including initial and repeat courses; and for the prevention of postoperative nausea and vomiting. Dolasetron is a highly specific and selective serotonin 5-HT3 receptor antagonist. The serotonin 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 thought that chemotherapeutic agents produce nausea and vomiting by releasing serotonin from the enterochromaffin cells of the small intestine, and that the released serotonin then activates 5-HT3 receptors located on vagal efferents to initiate the vomiting reflex. This drug is not shown to have activity at other known serotonin receptors, and has low affinity for dopamine receptors. Dolasetron mesilate is rapidly reduced by carbonyl reductase to form its major pharmacologically active metabolite reduced dolasetron. In addition dolasetron was in the phase III clinical trials for the investigation, that intravenous using of dolasetron mesilate reduces pain intensity in patients with fibromyalgia.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Serotonin 3a (5-HT3a) receptor 46 Target ID: CHEMBL1899 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9341357	Antagonist 2778

Conditions

Condition	Modality	Highest Phase	Product
Postoperative nausea and vomiting 29 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020623s008lbl.pdf	Preventing	Approved 8429	ANZEMET Approved Use ANZEMET Tablets are indicated for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy, including initial and repeat courses in adults and children 2 years and older. Launch Date 1997
Nausea and vomiting associated with moderately emetogenic cancer chemotherapy 3 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020623s008lbl.pdf	Preventing	Approved 8429	ANZEMET Approved Use ANZEMET Tablets are indicated for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy, including initial and repeat courses in adults and children 2 years and older. Launch Date 1997
Fibromyalgia 89 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21036635	Palliative	Phase III 656	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
320 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020623s010lbl.pdf%2C020624s023lbl.pdf	100 mg single, intravenous dose: 100 mg route of administration: Intravenous experiment type: SINGLE co-administered:		HYDRODOLASETRON plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
556 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020623s010lbl.pdf%2C020624s023lbl.pdf	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:		HYDRODOLASETRON plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
7.3 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020623s010lbl.pdf%2C020624s023lbl.pdf	100 mg single, intravenous dose: 100 mg route of administration: Intravenous experiment type: SINGLE co-administered:		HYDRODOLASETRON plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
8.1 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020623s010lbl.pdf%2C020624s023lbl.pdf	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:		HYDRODOLASETRON plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
27% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020623s010lbl.pdf%2C020624s023lbl.pdf	100 mg single, intravenous dose: 100 mg route of administration: Intravenous experiment type: SINGLE co-administered:		HYDRODOLASETRON plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
200 mg single, intravenous Highest studied dose Dose: 200 mg Route: intravenous Route: single Dose: 200 mg Sources: https://pubmed.ncbi.nlm.nih.gov/10086835 Page: p.33	healthy, 19 - 45 n = 24 Health Status: healthy Age Group: 19 - 45 Sex: M Population Size: 24 Sources: https://pubmed.ncbi.nlm.nih.gov/10086835 Page: p.33	Other AEs: Defect conduction intraventricular... Other AEs: Defect conduction intraventricular Sources: https://pubmed.ncbi.nlm.nih.gov/10086835 Page: p.33
200 mg single, oral Highest studied dose Dose: 200 mg Route: oral Route: single Dose: 200 mg Sources: https://pubmed.ncbi.nlm.nih.gov/10086835 Page: p.33	healthy, 19 - 45 n = 24 Health Status: healthy Age Group: 19 - 45 Sex: M Population Size: 24 Sources: https://pubmed.ncbi.nlm.nih.gov/10086835 Page: p.33	Other AEs: Defect conduction intraventricular... Other AEs: Defect conduction intraventricular Sources: https://pubmed.ncbi.nlm.nih.gov/10086835 Page: p.33
100 mg single, oral Recommended Dose: 100 mg Route: oral Route: single Dose: 100 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020623s010lbl.pdf%2C020624s023lbl.pdf Page: p.5	unhealthy Health Status: unhealthy Condition: Nausea and vomiting associated with cancer chemotherapy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020623s010lbl.pdf%2C020624s023lbl.pdf Page: p.5	Other AEs: QT interval prolonged, Torsade de pointes... Other AEs: QT interval prolonged Torsade de pointes PR interval prolonged QRS prolonged Atrioventricular block (grade 3-5) Cardiac arrest (grade 3-5) Arrhythmia ventricular (grade 3-5) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020623s010lbl.pdf%2C020624s023lbl.pdf Page: p.5

AEs

AE	Significance	Dose	Population
Defect conduction intraventricular		200 mg single, intravenous Highest studied dose Dose: 200 mg Route: intravenous Route: single Dose: 200 mg Sources: https://pubmed.ncbi.nlm.nih.gov/10086835 Page: p.33	healthy, 19 - 45 n = 24 Health Status: healthy Age Group: 19 - 45 Sex: M Population Size: 24 Sources: https://pubmed.ncbi.nlm.nih.gov/10086835 Page: p.33
Defect conduction intraventricular		200 mg single, oral Highest studied dose Dose: 200 mg Route: oral Route: single Dose: 200 mg Sources: https://pubmed.ncbi.nlm.nih.gov/10086835 Page: p.33	healthy, 19 - 45 n = 24 Health Status: healthy Age Group: 19 - 45 Sex: M Population Size: 24 Sources: https://pubmed.ncbi.nlm.nih.gov/10086835 Page: p.33
PR interval prolonged		100 mg single, oral Recommended Dose: 100 mg Route: oral Route: single Dose: 100 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020623s010lbl.pdf%2C020624s023lbl.pdf Page: p.5	unhealthy Health Status: unhealthy Condition: Nausea and vomiting associated with cancer chemotherapy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020623s010lbl.pdf%2C020624s023lbl.pdf Page: p.5
QRS prolonged		100 mg single, oral Recommended Dose: 100 mg Route: oral Route: single Dose: 100 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020623s010lbl.pdf%2C020624s023lbl.pdf Page: p.5	unhealthy Health Status: unhealthy Condition: Nausea and vomiting associated with cancer chemotherapy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020623s010lbl.pdf%2C020624s023lbl.pdf Page: p.5
QT interval prolonged		100 mg single, oral Recommended Dose: 100 mg Route: oral Route: single Dose: 100 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020623s010lbl.pdf%2C020624s023lbl.pdf Page: p.5	unhealthy Health Status: unhealthy Condition: Nausea and vomiting associated with cancer chemotherapy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020623s010lbl.pdf%2C020624s023lbl.pdf Page: p.5
Torsade de pointes		100 mg single, oral Recommended Dose: 100 mg Route: oral Route: single Dose: 100 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020623s010lbl.pdf%2C020624s023lbl.pdf Page: p.5	unhealthy Health Status: unhealthy Condition: Nausea and vomiting associated with cancer chemotherapy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020623s010lbl.pdf%2C020624s023lbl.pdf Page: p.5
Arrhythmia ventricular	grade 3-5	100 mg single, oral Recommended Dose: 100 mg Route: oral Route: single Dose: 100 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020623s010lbl.pdf%2C020624s023lbl.pdf Page: p.5	unhealthy Health Status: unhealthy Condition: Nausea and vomiting associated with cancer chemotherapy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020623s010lbl.pdf%2C020624s023lbl.pdf Page: p.5
Atrioventricular block	grade 3-5	100 mg single, oral Recommended Dose: 100 mg Route: oral Route: single Dose: 100 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020623s010lbl.pdf%2C020624s023lbl.pdf Page: p.5	unhealthy Health Status: unhealthy Condition: Nausea and vomiting associated with cancer chemotherapy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020623s010lbl.pdf%2C020624s023lbl.pdf Page: p.5
Cardiac arrest	grade 3-5	100 mg single, oral Recommended Dose: 100 mg Route: oral Route: single Dose: 100 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020623s010lbl.pdf%2C020624s023lbl.pdf Page: p.5	unhealthy Health Status: unhealthy Condition: Nausea and vomiting associated with cancer chemotherapy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020623s010lbl.pdf%2C020624s023lbl.pdf Page: p.5

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737		substrate 1217	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	CYP3A 191 UGT 192 FMO 35

Drug as victim

Target	Modality	Activity
CYP2D6 1217	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020623s012lbl.pdf#page=2 Page: 2.0	yes
CYP3A 191	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020623s012lbl.pdf#page=2 Page: 2.0	yes
CYP3A4 1737	substrate 3367 Sources: https://dmd.aspetjournals.org/content/24/5/602.short	yes
FMO 35	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/16192915/	yes
UGT 192	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020623s012lbl.pdf#page=2 Page: 2.0	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://pubmed.ncbi.nlm.nih.gov/11046096/

Sourcing

Vendor/Aggregator	ID	URL
AstaTech	C71510
BOC Sciences	115956-12-2
MolPort	MolPort-046-851-633
PI Chemicals	PI-21727
Sigma Aldrich	CDS021594
Vesino Industrial Co Ltd	VA10755
ZINC	ZINC000000897298	http://zinc15.docking.org/substances/ZINC000000897298
eMolecules	195187818
mcule	MCULE-2311889447

PubMed

Title	Date	PubMed
5-HT(3)-receptor antagonists for the treatment of nausea and vomiting: a reappraisal of their side-effect profile.	2002	12401905
A systematic approach to the management of postoperative nausea and vomiting.	2002 Dec	12476402
Ondansetron and dolasetron provide equivalent postoperative vomiting control after ambulatory tonsillectomy in dexamethasone-pretreated children.	2002 Nov	12401599
Compatibility and stability of 5-HT3 receptor antagonists: a pharmacology review.	2002 Nov-Dec	12432417
5-HT3-receptor antagonists and the cytochrome P450 system: clinical implications.	2002 Sep-Oct	12416899
Binding interactions of antagonists with 5-hydroxytryptamine3A receptor models.	2003	14626451
Benefits and risks of newer treatments for chemotherapy-induced and postoperative nausea and vomiting.	2003	12608887
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.	2003 Dec 1	14635083
Antiemetic prophylaxis for office-based surgery: are the 5-HT3 receptor antagonists beneficial?	2003 Feb	12552184
Dolasetron prophylaxis reduces nausea and postanaesthesia recovery time after remifentanil infusion during monitored anaesthesia care for extracorporeal shock wave lithotripsy.	2003 Feb	12538377
[Blocking nociceptive afferents by retrobulbar bupivacaine does not decrease nausea and vomiting after propofol-remifentanil anaesthesia].	2003 Nov	14600858
Randomized, double-blind trial of dolasetron versus droperidol for prophylaxis of postoperative nausea and vomiting in patients undergoing TRAM flap breast reconstruction surgery.	2003 Nov	14595183
Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome p450 3A4 substrate, in patients with chronic myeloid leukaemia.	2003 Nov 17	14612892
Comparison of oral dolasetron and ondansetron in the prophylaxis of postoperative nausea and vomiting in children.	2003 Oct	14580054
Electrocardiographic and cardiovascular effects of the 5-hydroxytryptamine3 receptor antagonists.	2003 Sep	12921512
Impact of nausea and vomiting on quality of life in cancer patients during chemotherapy.	2003 Sep 17	14521717
Same old story? Do we need to modify our supportive care treatment of elderly cancer patients? Focus on antiemetics.	2004	15493948
Palonosetron.	2004	15139789
Ondansetron versus dolasetron: a comparison study in the prevention of postoperative nausea and vomiting in patients undergoing gynecological procedures.	2004 Apr	15098526
Intra-arterial induction high-dose chemotherapy with cisplatin for oral and oropharyngeal cancer: long-term results.	2004 Apr 5	15054449
Timing of administration of dolasetron affects dose necessary to prevent postoperative nausea and vomiting.	2004 Aug	15374558
Droperidol and dolasetron alone or in combination for prevention of postoperative nausea and vomiting after vitrectomy.	2004 Aug	15288990
Carbonyl reduction of naltrexone and dolasetron by oxidoreductases isolated from human liver cytosol.	2004 Dec	15563768
Gateways to clinical trials.	2004 Jan-Feb	14988742
A comparison of infraclavicular nerve block versus general anesthesia for hand and wrist day-case surgeries.	2004 Jul	15220781
Granisetron vs dolasetron for acute chemotherapy-induced nausea and vomiting (CINV) in high and moderately high emetogenic chemotherapy: an open-label pilot study.	2004 Jun	15200746
Is amiodarone a safe antiarrhythmic to use in supraventricular tachyarrhythmias after lung cancer surgery?	2004 Jun 11	15191616
Palonosetron: a unique 5-HT3 receptor antagonist indicated for the prevention of acute and delayed chemotherapy-induced nausea and vomiting.	2004 May	16163194
5-HT3 receptor antagonists for prevention of late acute-onset emesis.	2004 Oct	15316106
Single-dose parenteral pharmacological interventions for the prevention of postoperative shivering: a quantitative systematic review of randomized controlled trials.	2004 Sep	15333401
The utility of antiemetics in the prevention and treatment of postoperative nausea and vomiting in patients scheduled for laparoscopic cholecystectomy.	2005	16178752
Dolasetron versus ondansetron for the treatment of postoperative nausea and vomiting.	2005 Feb	15673860
Acute emesis: moderately emetogenic chemotherapy.	2005 Feb	15565276
Prediction of genotoxicity of chemical compounds by statistical learning methods.	2005 Jun	15962942
Prevention and treatment of postoperative nausea and vomiting.	2005 Jun 15	15947124
Prophylactic intravenous ondansetron and dolasetron in intrathecal morphine-induced pruritus: a randomized, double-blinded, placebo-controlled study.	2005 Nov	16244023
Employment of substandard antiemetic prophylaxis in recent trials of chemotherapy-induced nausea and vomiting.	2005 Nov	16204394
Cytochrome P450 2D6 metabolism and 5-hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting.	2005 Oct	16192915
Antiemetics of the 5-hydroxytryptamine 3A antagonist class inhibit muscle nicotinic acetylcholine receptors.	2005 Sep	16115980
Dolasetron and peri-operative cardiac arrhythmia.	2005 Sep	16115265
Paravertebral blocks provide superior same-day recovery over general anesthesia for patients undergoing inguinal hernia repair.	2006 Apr	16551902
Measuring the maintenance of daily life activities using the functional living index-emesis (FLIE) in patients receiving moderately emetogenic chemotherapy.	2006 Jan	16444851
Laparoscopic cholecystectomy and management of biliary tract stones in a freestanding ambulatory surgery center.	2006 Jan-Mar	16709357
Lack of effect of aprepitant on hydrodolasetron pharmacokinetics in CYP2D6 extensive and poor metabolizers.	2006 Jul	16809805
Meta-analysis of the use of rescue antiemetics following PONV prophylactic failure with 5-HT3 antagonist/dexamethasone versus single-agent therapies.	2006 May	16670361
Acute gastroenteritis in children: role of anti-emetic medication for gastroenteritis-related vomiting.	2007	17523698
Management of radiation-induced nausea and vomiting.	2007 Apr	17379085
Tremor in multiple sclerosis.	2007 Feb	17318714
Systemic anticancer therapy in gynecological cancer patients with renal dysfunction.	2007 Jul-Aug	17309673
[Prevention and treatment of postoperative nausea and vomiting in children. An evidence-based approach].	2007 Jun	17521856

Patents

Sample Use Guides

In Vivo Use Guide

Prevention of Cancer Chemotherapy-Induced Nausea and Vomiting. Adults: the recommended oral dosage of ANZEMET (dolasetron mesylate) is 100 mg given within one hour before chemotherapy. Pediatric Patients: the recommended oral dosage in pediatric patients 2 to 16 years of age is 1.8 mg/kg given within one hour before chemotherapy, up to a maximum of 100 mg. Prevention of Postoperative Nausea and Vomiting. Adults: the recommended oral dosage of ANZEMET (dolasetron mesylate) is 100 mg within two hours before surgery. Pediatric Patients: the recommended oral dosage in pediatric patients 2 to 16 years of age is 1.2 mg/kg given within two hours before surgery, up to a maximum of 100 mg. Safety and effectiveness in pediatric patients under 2 years of age have not been established. fibromyalgia: dolasetron (n = 29) 12.5mg/d via the intravenous route on 4 days at baseline (M0), 1 month (M1), 2 months (M2) and 3 months (M3) with follow-up to month 12.

Route of Administration: Other

In Vitro Use Guide

Unknown

Name

Type

Language

DOLASETRON

Official Name

English

dolasetron [INN]

Common Name

English

INDOLE-3-CARBOXYLIC ACID, ESTER WITH (8R)-HEXAHYDRO-8-HYDROXY-2,6-METHANO-2H-QUINOLIZIN-3(4H)-ONE

Common Name

English

Dolasetron [WHO-DD]

Common Name

English

1H-INDOLE-3-CARBOXYLIC ACID, OCTAHYDRO-3-OXO-2,6-METHANO-2H-QUINOLIZIN-8-YL ESTER, (2.ALPHA.,6.ALPHA.,8.ALPHA.,9A.BETA.)-

Common Name

English

DOLASETRON [MI]

Common Name

English

DOLASETRON [VANDF]

Common Name

English

DOLASETRON [HSDB]

Common Name

English

Classification Tree Code System Code

NDF-RT

N0000175817