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 2760

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 8360	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 8.7393599E11
Nausea and vomiting associated with moderately emetogenic cancer chemotherapy 3 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020623s008lbl.pdf	Preventing	Approved 8360	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 8.7393599E11
Fibromyalgia 89 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21036635	Palliative	Phase III 663	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 1709		substrate 1193	inhibitor 1599

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	CYP3A 189 UGT 187 FMO 35

Drug as victim

Target	Modality	Activity
CYP2D6 1193	substrate 3326 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020623s012lbl.pdf#page=2 Page: 2.0	yes
CYP3A 189	substrate 3326 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020623s012lbl.pdf#page=2 Page: 2.0	yes
CYP3A4 1709	substrate 3326 Sources: https://dmd.aspetjournals.org/content/24/5/602.short	yes
FMO 35	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/16192915/	yes
UGT 187	substrate 3326 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 1632	inhibitor 1613 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
Spectrum of use and tolerability of 5-HT3 receptor antagonists.	2004	15515406
Same old story? Do we need to modify our supportive care treatment of elderly cancer patients? Focus on antiemetics.	2004	15493948
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
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
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
Selective serotonin 5-HT3 receptor antagonists for postoperative nausea and vomiting: are they all the same?	2005	15740177
Pharmacokinetics of palonosetron in combination with aprepitant in healthy volunteers.	2005 Apr	15899109
Treatment of postoperative nausea and vomiting with dolasetron versus ondansetron: is there a conflict of interest?	2005 Dec	16301287
Coronary vasospasm leading to an acute myocardial infarction after the administration of dolasetron.	2005 Feb	15721735
Dolasetron versus ondansetron for the treatment of postoperative nausea and vomiting.	2005 Feb	15673860
Acute emesis: moderately emetogenic chemotherapy.	2005 Feb	15565276
5-hydroxytryptamine type-3 receptor antagonists for chemotherapy-induced and radiotherapy-induced nausea and emesis: can we safely reduce the dose of administered agents?	2005 Jul 1	15929119
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
Docetaxel (Taxotere), cisplatin, UFT, and leucovorin combination chemotherapy in advanced gastric cancer.	2005 Mar 14	15726097
The Breast Journal regrettably is retracting a manuscript entitled, " Dolasetron decreases postoperative nausea and vomiting after breast surgery".	2005 Mar-Apr	16363099
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
Prophylaxis of postoperative nausea and vomiting in patients scheduled for breast surgery.	2006	17163275
Prevention of postoperative nausea and vomiting with granisetron and dolasetron in relation to CYP2D6 genotype.	2006 Apr	16551910
Paravertebral blocks provide superior same-day recovery over general anesthesia for patients undergoing inguinal hernia repair.	2006 Apr	16551902
Systematic review on the recurrence of postoperative nausea and vomiting after a first episode in the recovery room - implications for the treatment of PONV and related clinical trials.	2006 Dec 13	17166262
The role of 5-HT3 receptor antagonists in preventing postoperative nausea and vomiting.	2006 Jan	16528908
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
Drugs for preventing postoperative nausea and vomiting.	2006 Jul 19	16856030
Relative efficacy of ondansetron, granisetron, dolasetron and palonosetron in controlling acute nausea and vomiting associated with platinum-based chemotherapy.	2006 Jun	16984743
Anesthesiologists' practice patterns for treatment of postoperative nausea and vomiting in the ambulatory Post Anesthesia Care Unit.	2006 Jun 1	16740165
New antiemetic drugs.	2006 Mar	16608997
Purification and characterization of akr1b10 from human liver: role in carbonyl reduction of xenobiotics.	2006 Mar	16381663
Meta-analysis of the use of rescue antiemetics following PONV prophylactic failure with 5-HT3 antagonist/dexamethasone versus single-agent therapies.	2006 May	16670361
Meta-analysis of the safety of 5-HT3 antagonists with dexamethasone or droperidol for prevention of PONV.	2006 May	16670360
Prophylaxis of postoperative vomiting in children undergoing tonsillectomy: a systematic review and meta-analysis.	2006 Nov	17005507
Inspired oxygen fraction of 0.8 compared with 0.4 does not further reduce postoperative nausea and vomiting in dolasetron-treated patients undergoing laparoscopic cholecystectomy.	2006 Nov	16963789
Palonosetron: a second-generation 5-hydroxytryptamine receptor antagonist.	2006 Oct	17026451
Dolasetron versus ondansetron as single-agent prophylaxis for patients at increased risk for postoperative nausea and vomiting: a prospective, double-blind, randomized trial.	2006 Sep	17036618
New approaches to chemotherapy-induced nausea and vomiting: from neuropharmacology to clinical investigations.	2006 Sep-Oct	17034670
Randomized comparison of two anti-emetic strategies in high-risk patients undergoing day-case gynaecological surgery.	2007 Apr	17317757
[Dolasetron and shivering. A prospective randomized placebo-controlled pharmaco-economic evaluation].	2007 Jan	17021884
Systemic anticancer therapy in gynecological cancer patients with renal dysfunction.	2007 Jul-Aug	17309673

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