[(3S,7R)-10-oxo-8-azatricyclo[5.3.1.03,8]undecan-5-yl] 1H-indole-3-carboxylate - CAS号 115956-12-2

物化性质

熔点：

278 ºC
沸点：

535.1±50.0 °C(Predicted)
密度：

1.37±0.1 g/cm3(Predicted)
溶解度：

可溶于氯仿（少量）、DMSO（少量）、甲醇（少量）
蒸汽压力：

1.7X10-9 mm Hg at 25 °C (est)

计算性质

辛醇/水分配系数(LogP)：

3.4
重原子数：

24
可旋转键数：

3
环数：

6.0
sp3杂化的碳原子比例：

0.47
拓扑面积：

62.4
氢给体数：

1
氢受体数：

4

ADMET

代谢

肝脏的

Hepatic

来源:DrugBank

代谢

生物转化是肝脏介导的，并且是完整的，主要转化为活性代谢物氢多拉赛吨（通过普遍存在的酶，羰基还原酶）。进一步的羟基化由细胞色素P450 CYP2D6介导，而进一步的N-氧化则由CYP3A和黄素单加氧酶共同介导。

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.

来源:Hazardous Substances Data Bank (HSDB)

代谢

盐酸多拉司琼的代谢在六名健康男性志愿者中进行研究，这些志愿者单次口服了300毫克的[14C]多拉司琼甲磺酸盐。平均来看，总放射活性的59%在尿液中回收，25%在粪便中。在给药后长达36小时内收集的尿样中定量了代谢物。还原型多拉司琼（RD）在尿液中的剂量占比为17-54%。RD的羟基代谢物在尿液中的剂量不超过9%。剩余的尿液中放射性大部分是由RD和羟基RD的共轭代谢物组成。对选定的尿液样本进行水解实验表明，RD的葡萄糖苷酸是尿液中含量最丰富的共轭物。尿液中有一小部分剂量（<1%）被确认为RD的N-氧化物。通过手性HPLC分析尿液样本，表明RD的R（+）：S（-）比例大约为9:1。

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.

来源:Hazardous Substances Data Bank (HSDB)

代谢

多拉塞曲恩（dolasetron）或MDL 73,147EF [(2 alpha, 6 alpha, 8 alpha, 9a beta)-八氢-3-氧代-2,6-亚甲基-2H-喹诺里嗪-8-基-1H-吲哚-3-羧酸甲烷磺酸盐]的代谢初始步骤是还原前手性羰基，产生手性二级醇“还原多拉塞曲恩”。已经开发并使用了一种高效液相色谱法（HPLC），使用手性柱来分离还原多拉塞曲恩对映体，并用于测量在大鼠、狗和人体内给予多拉塞曲恩后尿液中的对映体。在所有情况下，还原对(+)-(R)-对映体具有对映选择性，尽管狗在静脉给药后显示出较低的对映选择性。在大鼠和人体尿液中，大约找到90:10的对映体比率(+/-)。由于初步研究表明，人肝微粒体对对映体醇的氧化只表现出轻微的对映选择性，因此进一步代谢对此对映体比率的影响被认为很小。从体外研究中获得了立体选择性还原在人中的作用，其中多拉塞曲恩与人全血孵育。在人体全血中形成的还原多拉塞曲恩的对映体组成与给予多拉塞曲恩后在人体尿液中发现的相同。对映选择性不是由于对映体在吸收、分布、代谢或排泄方面的差异，因为给大鼠和狗静脉或口服给予消旋还原多拉塞曲恩后，在尿液中回收的基本上与给药剂量的对映体组成相同。幸运的是，(+)-(R)-对映体主要通过羰基还原酶形成，因为它是最活跃的化合物。

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.

来源:Hazardous Substances Data Bank (HSDB)

代谢

多拉赛曲伦已知的人体代谢物包括还原型多拉赛曲伦。

Dolasetron has known human metabolites that include Reduced dolasetron.

来源:NORMAN Suspect List Exchange

毒理性

药物性肝损伤

药物：多拉司琼

Compound:dolasetron