5-HT₃ Receptor

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.
Orally-administered dolasetron intravenous solution and tablets are bioequivalent.
The apparent absolute bioavailability of oral dolasetron is approximately 75%. Food does not affect the bioavailability of dolasetron taken by mouth.
Time to peak plasma concentration /for hydrodolasetron/ following oral administration /was/ approximately 1 hour and following intravenous injection /was/ 0.6 hours.
For more Absorption, Distribution and Excretion (Complete) data for DOLASETRON (15 total), please visit the HSDB record page.

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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.
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.
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.
Dolasetron has known human metabolites that include Reduced dolasetron.

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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.
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 ...

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Little information is available on the use of dolasetron during breastfeeding. Until more data become available, dolasetron should be used with caution during breastfeeding. An alternate drug may be preferred.
◉ Effects in Breastfed Infants
A double-blind study randomized 160 women receiving an elective cesarean section under spinal anesthesia to receive either sufentanil for patient-controlled intravenous analgesia (standard care) or standard care plus dexmedetomidine. Dexmedetomidine was given as 5 mcg/kg, followed by a continuous infusion of 0.5 mcg/kg per hour until the end of surgery. Patient in this latter group received dexmedetomidine plus sufentanil for patient-controlled intravenous analgesia postoperatively for 2 days. Both groups had 25 mg of dolasetron added to the patient-controlled intravenous analgesia solution and all mothers breastfed their infants. Both groups had good neonatal behavioral neurological assessments on days 1 and 2 postpartum.[1]
◉ Effects on Lactation and Breastmilk
A double-blind study randomized 160 women receiving an elective cesarean section under spinal anesthesia to receive either sufentanil for patient-controlled intravenous analgesia (standard care) or standard care plus dexmedetomidine. Dexmedetomidine was given as 5 mcg/kg, followed by a continuous infusion of 0.5 mcg/kg per hour until the end of surgery. Patient in this latter group received dexmedetomidine plus sufentanil for patient-controlled intravenous analgesia postoperatively for 2 days. Both groups had 25 mg of dolasetron added to the patient-controlled intravenous analgesia solution. Patients who received dexmedetomidine had a shorter time to the first lactation (28 vs 34 hours), achieved exclusive breastfeeding sooner (8 vs 11 days) and had a greater amount of milk on the second day postpartum.[1]

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Interactions
Concurrent use of cimetidine, which is a nonselective cytochrome P450 enzyme inhibitor, with dolasetron for 7 days has been found to result in a 24% increase in hydrodolasetron blood concentrations.
Concurrent use of intravenous dolasetron and atenolol has been found to result in a 27% decrease in clearance hydrodolasetron.

[1]. 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.

LSM-5418 is an indolyl carboxylic acid.
Dolasetron is a Serotonin-3 Receptor Antagonist. The mechanism of action of dolasetron is as a Serotonin 3 Receptor Antagonist.
See also: Dolasetron (annotation moved to).

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

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

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Drug Warnings
/Administration is contraindicated in patients with/ known hypersensitivity to dolasetron mesylate.
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.
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.
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.
For more Drug Warnings (Complete) data for DOLASETRON (7 total), please visit the HSDB record page.

C19H20N2O3

324.3737

324.147

C, 70.35; H, 6.21; N, 8.64; O, 14.80

115956-12-2

Dolasetron Mesylate hydrate; 878143-33-0; Dolasetron Mesylate; 115956-13-3; Dolasetron-d4

3033818

White to off-white solid powder

1.37 g/cm3

535.1ºC at 760 mmHg

278 ºC

277.4ºC

4.08E-10mmHg at 25°C

1.76

2.456

62.4

1

4

3

24

535

2

O(C(C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12)=O)C1([H])C([H])([H])[C@]2([H])C([H])([H])C3([H])C(C([H])([H])N2C([H])(C1([H])[H])C3([H])[H])=O

UKTAZPQNNNJVKR-AKJUYKBHSA-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?

[(3S,7R)-10-oxo-8-azatricyclo[5.3.1.03,8]undecan-5-yl] 1H-indole-3-carboxylate

Dolasetronum; HSDB 7565; HSDB-7565; HSDB7565; Dolasetron

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 本产品在运输和储存过程中需避光。

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

DMSO: ~64 mg/mL (~197.3 mM)

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
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