QuickView for Dolasetron (compound)

Summary
General Info

PubChem

PubChem Compound 11503972

Name:	dolasetron mesylate
PubChem Compound ID:	11503972
Molecular formula:	C₁₉H₂₀N₂O₃
Molecular weight:	324.374 g/mol

DrugBank

Identification

Name:	dolasetron mesylate
Name (isomeric):	DB00757
Drug Type:	small molecule
Brand:	Dolasetronum [INN-Latin], Anzemet, Dolasteron
Category:	Serotonin Antagonists, Antiemetics
CAS number:	115956-12-2

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.
Pharmacology:	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 ... show more » 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. show less «
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 p... show more » 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. show less «
Absorption:	Orally-administered dolasetron is well absorbed
Protein binding:	69-77%
Biotransformation:	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]
Affected organisms:	Humans and other mammals

Interactions

Food interaction:

Take without regard to meals.

Drug interaction:

Tacrolimus	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Thiothixene	May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.
Vorinostat	Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Toremifene	Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.
Zuclopenthixol	Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Targets

5-hydroxytryptamine 3 receptor

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

UniProt ID:

P46098

Gene:

HTR3A

Actions:

antagonist

References:

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5.
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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.
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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.
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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.
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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.
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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.
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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.
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Hui YF, Ignoffo RJ: Dolasetron. A new 5-hydroxytryptamine3 receptor antagonist. Cancer Pract. 1997 Sep-Oct;5(5):324-8.
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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.
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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.
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Enzymes

Cytochrome P450 3A4

Cytochrome P450 2D6

Cytochrome P450 2C9