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CAS 115956-12-2
Also known as: Dolasetron, 115956-12-2, Hsdb 7565, Dolasetronum [inn-latin], Dolasetron [inn:ban], 82wi2l7q6e
Molecular Formula
C19H20N2O3
Molecular Weight
324.4  g/mol
InChI Key
UKTAZPQNNNJVKR-UDXKHGJESA-N

Dolasetron is an indole derivative and a potent serotonin 5-HT3 receptor antagonist with anti-emetic property. Dolasetron blocks the activity of serotonin released from the enterochromaffin cells of the small intestine by selectively inhibiting and inactivating 5-HT3 receptors located on the nerve terminals of the vagus nerve in the periphery and centrally in the chemoreceptor trigger zone of the area postrema. This results in suppression of signalling to trigger chemo- and radiotherapy induced nausea and vomiting.
1 2D Structure

CAS 115956-12-2

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
[(7S)-10-oxo-8-azatricyclo[5.3.1.03,8]undecan-5-yl] 1H-indole-3-carboxylate
2.1.2 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?/m0/s1
2.1.3 InChI Key
UKTAZPQNNNJVKR-UDXKHGJESA-N
2.1.4 Canonical SMILES
C1C2CC3CC(CC1N3CC2=O)OC(=O)C4=CNC5=CC=CC=C54
2.1.5 Isomeric SMILES
C1[C@H]2CC(CC3N2CC(=O)C1C3)OC(=O)C4=CNC5=CC=CC=C54
2.2 Synonyms
2.2.1 MeSH Synonyms

1. 1h-indole-3-carboxylic Acid, (6r,9as)-octahydro-3-oxo-2,6-methano-2h-quinolizin-8-yl Ester, Rel-, Methanesulfonate, Hydrate (1:1:1)

2. 1h-indole-3-carboxylic Acid, Octahydro-3-oxo-2,6-methano-2h-quinolizin-8-yl Ester, (2-alpha,6-alpha,8-alpha,9a-beta)-

3. 1h-indole-3-carboxylic Acid-trans-octahydro-3-oxo-2,6-methano-2h-quinolizin-8-yl Ester Methanesulfonate

4. Anzemet

5. Dolasetron

6. Dolasetron Mesilate Monohydrate

7. Dolasetron Mesylate

8. Dolasetron Mesylate Monohydrate

9. Indole-3-carboxylic Acid, Ester With (8r)-hexahydro-8-hydroxy-2,6-methano-2h-quinolizin-3(4h)-one

10. Mdl 73,147ef

11. Mdl 73147ef

12. Mdl-73147ef

13. Octahydro-3-oxo-2,6-methano-2h-quinolizin-8-yl 1h-indole-3-carboxylate

2.2.2 Depositor-Supplied Synonyms

1. Dolasetron

2. 115956-12-2

3. Hsdb 7565

4. Dolasetronum [inn-latin]

5. Dolasetron [inn:ban]

6. 82wi2l7q6e

7. Unii-82wi2l7q6e

8. Chembl1237118

9. Hms2089n22

10. (2alpha,6alpha,8alpha,9abeta)-octahydro-3-oxo-2,6-methano-2h-quinolizin-8-yl-1h-indole-3-carboxylate

11. Ab01275480-01

12. 956d122

13. A900589

14. 1h-indole-3-carboxylic Acid, Octahydro-3-oxo-2,6-methano-2h-quinolizin-8-yl Ester, (2alpha,6alpha,8alpha,9abeta)-

2.3 Create Date
2007-02-09
3 Chemical and Physical Properties
Molecular Weight 324.4 g/mol
Molecular Formula C19H20N2O3
XLogP33.4
Hydrogen Bond Donor Count1
Hydrogen Bond Acceptor Count4
Rotatable Bond Count3
Exact Mass324.14739250 g/mol
Monoisotopic Mass324.14739250 g/mol
Topological Polar Surface Area62.4 Ų
Heavy Atom Count24
Formal Charge0
Complexity535
Isotope Atom Count0
Defined Atom Stereocenter Count1
Undefined Atom Stereocenter Count1
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Therapeutic Uses

Antiemetic

National Library of Medicine's Medical Subject Headings online file (MeSH, 1999)


Dolasetron injection is indicated for the prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including high-dose cisplatin. Dolasetron tablets are indicated for the prevention of nausea and vomiting associated with moderate-emetogenic cancer chemotherapy, including initial and repeat courses. /Included in US product label/

Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 1147


Dolasetron injection and tablets are indicated for the prevention of postoperative nausea and/or vomiting. Routine prophylaxis is not recommended when there is little risk of nausea and/or vomiting developing postoperatively, except in patients in whom nausea and/or vomiting must be avoided. /Included in US product label/

Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 1147


Dolasetron injection is indicated for the treatment of postoperative nausea and/or vomiting. /Included in US product label/

Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 1147


4.2 Drug Warning

/Administration is contraindicated in patients with/ known hypersensitivity to dolasetron mesylate.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2941


Acute, usually reversible ECG alterations and/or risk of altered cardiac conduction. Prolongation of PR, QTC, and JT intervals and widening of the QRS complex have been observed in patients receiving dolasetron therapy. These alterations, which are caused by prolongation of cardiac depolarization and repolarization, appear to be related to plasma concentrations of the active metabolite hydrodolasetron and generally are self-limiting as these concentrations decline. ECG interval prolongation rarely has resulted in heart block or cardiac arrhythmias. Sudden death has occurred in at least one patient 6 hours after receiving IV dolasetron (1.8 mg/kg), although the patient had other potential risk factors such as prior therapy with doxorubicin and concomitant cyclophosphamide.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2941


Dolasetron should be used with caution in patients who have or may develop prolongation of cardiac conduction intervals, particularly QTC, including those with congenital QT syndrome, those with uncorrected hypokalemia or hypomagnesemia, patients receiving diuretics that may induce electrolyte abnormalities, patients receiving antiarrhythmic agents or other drugs that alter cardiac conduction (e.g., prolong QT interval), and those receiving cumulative high-dose anthracycline therapy.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2941


Sensitivity reactions, including anaphylactic reaction, facial edema, and urticaria, have been reported rarely. Cross-sensitivity reactions have been reported in patients receiving other selective 5-HT3 receptor antagonists but have not been reported to date with dolasetron.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2941


For more Drug Warnings (Complete) data for DOLASETRON (7 total), please visit the HSDB record page.


5 Pharmacology and Biochemistry
5.1 MeSH Pharmacological Classification

Antiemetics

Drugs used to prevent NAUSEA or VOMITING. (See all compounds classified as Antiemetics.)


Serotonin 5-HT3 Receptor Antagonists

Drugs that bind to but do not activate SEROTONIN 5-HT3 RECEPTORS, thereby blocking the actions of SEROTONIN or SEROTONIN 5-HT3 RECEPTOR AGONISTS. (See all compounds classified as Serotonin 5-HT3 Receptor Antagonists.)


5.2 Absorption, Distribution and Excretion

Orally-administered dolasetron is well absorbed, but the parent drug is rarely detected in plasma due to rapid and complete metabolism to hydrodolasetron.

Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 1148


Orally-administered dolasetron intravenous solution and tablets are bioequivalent.

Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 1148


The apparent absolute bioavailability of oral dolasetron is approximately 75%. Food does not affect the bioavailability of dolasetron taken by mouth.

Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 1148


Time to peak plasma concentration /for hydrodolasetron/ following oral administration /was/ approximately 1 hour and following intravenous injection /was/ 0.6 hours.

Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 1148


For more Absorption, Distribution and Excretion (Complete) data for DOLASETRON (15 total), please visit the HSDB record page.


5.3 Metabolism/Metabolites

Biotransformation /is/ hepatic and complete, mainly to the active metabolite hydrodolasetron (by means of the ubiquitous enzyme, carbonyl reductase). Further hydroxylation is mediated by cytochrome P450 CYP2D6 and further N-oxidation by both CYP3A and flavin monooxygenase.

Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 1148


The metabolism of dolasetron mesylate was studied in six healthy male volunteers who were given a single 300 mg oral dose of [14C]dolasetron mesylate. An average of 59% of the total radioactivity was recovered in the urine and 25% in the feces. Metabolites were quantitated in urine samples taken up to 36 hr post-dose. Reduced dolasetron (RD) accounted for 17-54% of the dose in urine. Hydroxylated metabolites of RD made up no more than 9% of the dose in urine. Most of the remaining urinary radioactivity consisted of conjugated metabolites of RD and hydroxy RD. Hydrolysis of selected urine samples showed that the glucuronide of RD was the most abundant conjugate in urine. A small percentage of the dose (< 1%) in urine was identified as the N-oxide of RD. Analysis of urine samples by chiral HPLC indicated that the R(+):S(-) ratio of RD was approximately 9:1.

PMID:7493546 Reith MK, Sproles G et al; Drug Metab Dispos 23 (8): 806-12 (1995)


The initial step in the metabolism of dolasetron or MDL 73,147EF [(2 alpha, 6 alpha, 8 alpha, 9a beta)-octahydro-3-oxo-2,6-methano-2H- quinolizin-8-yl 1H-indol-3-carboxylate, monomethanesulfonate] is the reduction of the prochiral carbonyl group to give a chiral secondary alcohol "reduced dolasetron." An HPLC method, using a chiral column to separate reduced dolasetron enantiomers, has been developed and used to measure enantiomers in urine of rats, dogs, and humans after dolasetron administration. In all cases, the reduction was enantioselective for the (+)-(R)-enantiomer, although the dog showed lower stereoselectivity, especially after iv administration. An approximate enantiomeric ratio (+/-) of 90:10 was found in rat and human urine. The contribution of further metabolism to this enantiomeric ratio was considered small as preliminary studies showed that oxidation of the enantiomeric alcohols by human liver microsomes demonstrated only minor stereoselectivity. Further evidence for the role of stereoselective reduction in man was obtained from in vitro studies, where dolasetron was incubated with human whole blood. The enantiomeric composition of reduced dolasetron formed in human whole blood was the same as that found in human urine after administration of dolasetron. Enantioselectivity was not due to differences in the absorption, distribution, metabolism, or excretion of enantiomers, as iv or oral administration of rac-reduced dolasetron to rats and dogs lead to the recovery, in urine, of essentially the same enantiomeric composition as the dose administered. It is fortuitous that the (+)-(R)-enantiomer is predominantly formed by carbonyl reductase, as it is the more active compound.

PMID:7495640 Dow J, Berg C; Chirality 7 (5): 342-8 (1995)


5.4 Biological Half-Life

Following oral administration hydrodolasetron has a elimination half-life of 8.1 hours (mean). Following intravenous injection dolasetron /has a elimination half-life of/ less than 10 minutes. Hydrodolasetron /has a elimination half-life of/ 7.3 hours after intravenous injection of dolasetron.

Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 1148


Following intravenous administration to healthy male subjects of doses ranging from 0.6 to 5 mg/kg, dolasetron disappeared extremely rapidly from plasma; concentrations were generally measurable for only 2-4 hr. Less than 1 percent of the dose was excreted intact in urine. A major plasma metabolite, reduced dolasetron, peaked rapidly at approximately 0.625 hr (median). Its median terminal disposition half-life was 7.56 hr ...

PMID:1467456 Boxenbaum H, Gillespie T et al; Biopharm Drug Dispos 13 (9): 693-701 (1992)


5.5 Mechanism of Action

Dolasetron, and its active metabolite hydrodolasetron, are highly specific and selective antagonist of serotonin subtype 3 (5-HT3) receptors. 5-HT3 receptors are present peripherally on vagal nerve terminals and centrally in the area postrema of the brain. Chemotherapeutic medications appear to precipitate release of serotonin from the enterochromaffin cells of the small intestine, which activates 5-HT3 receptors on vagal efferents to initiate the vomiting reflex. Dolasetron has not been shown to have activity at other known serotonin receptors, and has low affinity for dopamine receptors.

Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 1147


Dolasetron causes dose-related acute, and usually reversible, electrocardiogram (ECG) changes including QRS widening and PR, QTc, and JT prolongation; QTc prolongation is caused primarily by QRS widening. Dolasetron seems to prolong both depolarization and,to a lesser extent, repolarization time, and its active metabolites may block sodium channels.

Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 1147


The active metabolite of dolasetron (i.e., hydrodolasetron) may block sodium channels and prolong cardiac depolarization and, to a lesser extent, repolarization time.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2941


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