5-Hydroxytryptamine-3 Receptor Antagonist (5-HT₃ RA). Dolasetron is a first-generation 5-HT₃ receptor antagonist used for the prevention of chemotherapy-induced nausea and vomiting (CINV). [1,2]

Dolasetron is a first-generation 5-HT₃ receptor antagonist that prevents chemotherapy-induced nausea and vomiting (CINV) by blocking serotonin binding to 5-HT₃ receptors in the gastrointestinal tract and central nervous system. [2]

Clinical Efficacy – Phase III Trials: In a pooled analysis of four phase III randomized, double-blind trials, dolasetron (100 mg IV) was evaluated in patients receiving moderately emetogenic chemotherapy (MEC). The complete response (CR) rate (no emesis and no rescue antiemetics) for dolasetron in the delayed phase (>24–120 h) was 45% (pooled across older 5-HT₃ RAs), which was significantly lower than the 57% CR rate observed with palonosetron (P < 0.0001). Similarly, the overall CR rate (0–120 h) was 40% for older 5-HT₃ RAs versus 51% for palonosetron (P < 0.0001). [2]
Clinical Efficacy – Retrospective Claims Analysis: In a retrospective database analysis of 26,974 patients receiving single-day emetogenic chemotherapy, dolasetron was among the 5-HT₃ RAs evaluated. The overall delayed CINV rate at cycle 1 was 15.6%, with dolasetron showing a rate of 17.3%. Compared to palonosetron, patients receiving dolasetron had higher odds of delayed CINV in cycle 2 (odds ratio [OR] = 1.65; 95% CI: 1.27–2.15; P = 0.002). This trend continued through subsequent cycles, though not all ORs reached statistical significance. Over 6 cycles of chemotherapy, dolasetron was associated with an additional $148,960 in CINV-related charges compared to palonosetron. [1]
Clinical Safety: The incidence of treatment-related adverse events (AEs) with dolasetron was 27.5% (pooled across older 5-HT₃ RAs), similar to palonosetron 0.25 mg (20.0%) and 0.75 mg (26.5%). The most common treatment-related AEs were constipation (9.2%) and headache (7.4%). [2]

We analyzed patient-level data derived from four randomized, double-blind, phase III studies that compared palonosetron at doses of 0.25 mg or 0.75 mg against ondansetron 32 mg, dolasetron 100 mg, or granisetron 40 μg/kg. The primary endpoints comprised complete response (CR), defined as no emesis and no use of rescue antiemetics, during the acute (0–24 h), delayed (>24–120 h), and overall (0–120 h) phases following chemotherapy. Additional endpoints included complete control (CC), characterized by no emesis, no rescue antiemetics, and no more than mild nausea, the number of emetic episodes, and the severity of nausea.

Absorption, Distribution and Excretion
Oral dolasetron is well absorbed, but due to its rapid and complete metabolism to hydrodolasetron, very little of the parent drug is detectable in plasma. Oral dolasetron is bioequivalent to intravenous and tablet formulations. The apparent absolute bioavailability of oral dolasetron is approximately 75%. Food does not affect the bioavailability of oral dolasetron. The time to peak plasma concentration after oral hydrodolasetron is approximately 1 hour, and after intravenous injection, approximately 0.6 hours. For more complete data on the absorption, distribution, and excretion of dolasetron (15 in total), please visit the HSDB record page. Metabolism/Metabolites Biotransformation occurs primarily in the liver and is complete, mainly converting to the active metabolite hydrodolasetron (via ubiquitous carbonyl reductases). Further hydroxylation is mediated by cytochrome P450 CYP2D6, and further N-oxidation is co-mediated by CYP3A and flavin monooxygenase. This study investigated the metabolism of dolasetron mesylate in six healthy male volunteers who received a single oral dose of 300 mg [14C]dolasetron mesylate. An average of 59% of the total radioactivity was recovered in urine and 25% in feces. Metabolites were quantitatively analyzed in urine samples collected within 36 hours of administration. Reduced dolasetron (RD) comprised 17–54% of the dose in urine. Hydroxylated metabolites of RD accounted for less than 9% of the urine. The remaining urinary radioactivity consisted primarily of bound metabolites of RD and hydroxyl RD. Hydrolysis analysis of some urine samples revealed that glucuronide of RD was the most abundant conjugate in urine. A small amount (<1%) of the drug in urine was identified as N-oxide of RD. Chiral high-performance liquid chromatography (HPLC) analysis of urine samples showed an R(+):S(-) ratio of approximately 9:1 for RD. The initial step in the metabolism of dolasetron or MDL 73,147EF [(2α,6α,8α,9αβ)-octahydro-3-oxo-2,6-methylene-2H-quinolazin-8-yl1H-indole-3-carboxylic acid ester, monomethylsulfonate] is the reduction of the prochiral carbonyl group to generate the chiral secondary alcohol, “reduced dolasetron.” An HPLC method using a chiral column has been developed to separate the enantiomers of reduced dolasetron and has been used to determine the enantiomers in the urine of rats, dogs, and humans after administration of dolasetron. In all cases, the reduction reaction was enantioselective to the (+)-(R)- enantiomer, although the stereoselectivity was lower in dogs, especially after intravenous administration. An enantiomer ratio of approximately 90:10 (+/-) was detected in the urine of both rats and humans. Since preliminary studies have shown that the oxidation of enantiomeric alcohols by human liver microsomes exhibits only slight stereoselectivity, the contribution of further metabolism to this enantiomer ratio is considered small. In vitro studies further confirmed the stereoselective reduction effect in humans by incubating dolasetron with human whole blood. The enantiomer composition of reduced dolasetron formed in human whole blood was identical to that found in human urine after dolasetron administration. The enantiomerism was not due to differences in the absorption, distribution, metabolism, or excretion of enantiomers, as the enantiomer composition recovered in urine after intravenous or oral administration of racemic reduced dolasetron to rats and dogs was substantially the same as that of the administered dose. Coincidentally, carbonyl reductase primarily generates the (+)-(R)- enantiomer because it is the more active compound. Known metabolites of dolasetron include reduced dolasetron. Biological half-life: After oral administration of hydrogenated dolasetron, the elimination half-life is 8.1 hours (mean). After intravenous injection of dolasetron, the elimination half-life is less than 10 minutes. The elimination half-life of dolasetron is 7.3 hours after intravenous administration. Following intravenous administration of 0.6 to 5 mg/kg of dolasetron to healthy male subjects, dolasetron rapidly disappears from the plasma; it is typically detectable only for 2–4 hours. Less than 1% of the dose is excreted unchanged in the urine. A major plasma metabolite, reduced dolasetron, rapidly reaches peak concentration at approximately 0.625 hours (median). Its median disposal half-life is 7.56 hours…

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Information regarding the use of dolasetron during lactation is limited. Until more data becomes available, caution should be exercised when using dolasetron during lactation. Alternative medications may be considered.
◉ Effects on Breastfed Infants
A double-blind study randomized 160 women undergoing elective cesarean section with spinal anesthesia to two groups. One group received patient-controlled intravenous analgesia (PCA) with sufentanil (standard treatment), while the other group received PCA with dexmedetomidine in addition to standard treatment. Dexmedetomidine was administered at a dose of 5 mcg/kg, followed by a continuous infusion at a rate of 0.5 mcg/kg/hour until the end of the procedure. The latter group received PCA with dexmedetomidine in combination with sufentanil for 2 days post-operatively. Both groups received 25 mg of dolasetron in their PCA solution, and all mothers breastfed. Both groups of newborns had good behavioral and neurological assessments on postpartum days 1 and 2. [1] ◉ Effects on lactation and breast milk A double-blind study randomized 160 women undergoing elective cesarean section under spinal anesthesia to two groups: one group received sufentanil patient-controlled intravenous analgesia (standard treatment), and the other group received dexmedetomidine in addition to standard treatment. The dose of dexmedetomidine was 5 mcg/kg, followed by continuous infusion at a rate of 0.5 mcg/kg/hour until the end of the surgery. The latter group received dexmedetomidine in combination with sufentanil patient-controlled intravenous analgesia 2 days postoperatively. Both groups had 25 mg dolasetron added to their patient-controlled intravenous analgesia solution. Patients treated with dexmedetomidine had a shorter time to first lactation (28 hours vs 34 hours), achieved exclusive breastfeeding faster (8 days vs 11 days), and had more milk production on the second postpartum day. [1]

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Drug Interactions
Studies have found that co-administration of cimetidine (a non-selective cytochrome P450 enzyme inhibitor) with dolasetron for 7 days resulted in a 24% increase in hydrodolasetron blood concentration.
Studies have found that co-administration of intravenous dolasetron with atenolol resulted in a 27% decrease in hydrodolasetron clearance.

[1].Faria C, et al. Outcomes Associated with 5-HT3-RA Therapy Selection in Patients with Chemotherapy-Induced Nausea and Vomiting: A Retrospective Claims Analysis. Am Health Drug Benefits. 2014 Jan;7(1):50-8.

[2]. Pooled analysis of phase III clinical studies of palonosetron versus ondansetron, dolasetron, and granisetron in the prevention of chemotherapy-induced nausea and vomiting (CINV). Support Care Cancer. 2014 Feb;22(2):469-77.

[3]. Long-term Use of Ondansetron, Dolasetron and Granisetron for the Prevention of Nausea and Vomiting: A Review of the Clinical Effectiveness and Safety [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2014 Apr 23. PMID: 25610941 Bookshelf ID: NBK269203

LSM-5418 is an indole carboxylic acid. Dolaseno is a serotonin 3 receptor antagonist. The mechanism of action of dolasetron is as a serotonin 3 receptor antagonist. See also: Dolaseno (note moved to). Mechanism of Action Dolaseno and its active metabolite, hydrogenated dolasetron, are specific and selective antagonists of the serotonin type 3 (5-HT3) receptor. 5-HT3 receptors are located in peripheral vagal nerve endings and the central posterior brain region. Chemotherapy drugs appear to induce the release of serotonin from enterochromaffin cells in the small intestine, thereby activating 5-HT3 receptors on vagal efferent fibers and initiating the vomiting reflex. Dolaseno has not been shown to be active against other known serotonin receptors and has a low affinity for dopamine receptors.
Dolasetron can cause dose-related acute electrocardiographic (ECG) changes, usually reversible, including QRS widening and prolongation of the PR, QTc, and JT intervals; QTc prolongation is primarily caused by QRS widening. Dolasetron appears to prolong depolarization and repolarization times (to a mild degree), and its active metabolite may block sodium channels.
The active metabolite of dolasetron (i.e., hydrogenated dolasetron) blocks sodium channels, prolonging cardiac depolarization and repolarization times (to a mild degree).
Therapeutic Uses
Antiemetic
Dolasetron injection is indicated for the prevention of nausea and vomiting associated with emetogenic chemotherapy for cancer (including high-dose cisplatin), whether in the initial or repeated course of chemotherapy. Dolasetron tablets are indicated for the prevention of nausea and vomiting induced by moderately emetogenic chemotherapy for cancer (including in the initial and repeated courses). /US Product Label/
Dolasetron injection and tablets are indicated for the prevention of postoperative nausea and/or vomiting. Routine prophylaxis is not recommended if the risk of postoperative nausea and/or vomiting is low, unless the patient must avoid nausea and/or vomiting. /US Product Label/
Dolasetron Injection is indicated for the treatment of postoperative nausea and/or vomiting. /US Product Label/

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Drug Warnings
/This drug is contraindicated in patients with known hypersensitivity to dolasetron mesylate.
There is a risk of acute, usually reversible, ECG changes and/or cardiac conduction abnormalities.Prolongation of the PR interval, QT interval, and JT interval, as well as QRS complex widening, has been observed in patients treated with dolasetron. These changes are caused by prolonged myocardial depolarization and repolarization, appear to be correlated with plasma concentrations of the active metabolite hydrodolasetron, and usually resolve spontaneously as these concentrations decrease. ECG interval prolongation rarely leads to cardiac conduction block or arrhythmias. At least one patient experienced sudden death 6 hours after receiving intravenous dolasetron (1.8 mg/kg), despite other potential risk factors such as prior doxorubicin treatment and concomitant cyclophosphamide use. Dolarasetron should be used with caution in patients with or at risk of prolonged cardiac conduction intervals (especially QT interval), including those with congenital QT syndrome, uncorrected hypokalemia or hypomagnesemia, those taking diuretics that may induce electrolyte disturbances, those taking antiarrhythmic drugs or other medications that alter cardiac conduction (e.g., prolonging the QT interval), and those receiving cumulative high-dose anthracyclines. Allergic reactions, including anaphylactic shock, facial edema, and urticaria, have been reported in rare cases. Cross-sensitivity reactions have been reported in patients receiving other selective 5-HT3 receptor antagonists, but no reports have been made with dolasetron to date. For more complete data on dolasetron (7 of 7), please visit the HSDB records page.

C20H24N2O6S

420.48

324.147

C, 57.13; H, 5.75; N, 6.66; O, 22.83; S, 7.62

115956-13-3

Dolasetron;115956-12-2;Dolasetron Mesylate hydrate;878143-33-0

3033818

Typically exists as solid at room temperature

535.1ºC at 760 mmHg

277.4ºC

1.65E-22mmHg at 25°C

2.977

1

4

3

24

535

2

O=C(C1=CNC2=C1C=CC=C2)O[C@@H]3C[C@@](CC4C5)([H])[N@](CC4=O)[C@@]5([H])C3.O=S(C)(O)=O

PSGRLCOSIXJUAL-PJAUNBIPSA-N

InChI=1S/C19H20N2O3.CH4O3S/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)171-5(2,3)4/h1-4,9,11-14,20H,5-8,10H21H3,(H,2,3,4)/t11?,12?,13?,14-

3-oxooctahydro-2H-2,6-methanoquinolizin-8-yl 1H-indole-3-carboxylate methanesulfonate

HSDB 7565; HSDB7565; DOLASETRON MESYLATE; Dalasetron Mesylate; 115956-13-3; Dolasetron (Mesylate); DTXSID3046827; HSDB-7565; MDL-73147; MDL 73147; MDL73147

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)