Cisatracurium | 96946-41-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: Cisatracurium
• 英文别名: 5-[3-[(1R,2R)-1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinolin-2-ium-2-yl]propanoyloxy]pentyl 3-[(1R,2R)-1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinolin-2-ium-2-yl]propanoate
• CAS: 96946-41-7
• 化学式: C53H72N2O12+2
• 分子量: 929.1
• InChiKey: YXSLJKQTIDHPOT-LJCJQEJUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.9
• 重原子数：
  67
• 可旋转键数：
  26
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.51
• 拓扑面积：
  126
• 氢给体数：
  0
• 氢受体数：
  12

ADMET

代谢

顺阿曲库铵的降解在很大程度上独立于肝脏代谢。顺阿曲库铵通过霍夫曼消除（一个依赖于pH和温度的化学反应）形成劳丹烷碱和单季铵盐丙烯酸代谢物。非特异性血浆酯酶将单季铵盐丙烯酸代谢物水解为单季铵盐醇代谢物（MQA）。MQA也可以通过霍夫曼消除，但这个过程的速度比检测到的顺阿曲库铵的速度慢。劳丹烷碱进一步代谢为去甲基代谢物，与葡萄糖醛酸结合并在尿液中排出。劳丹烷碱在给予几种动物时可能导致短暂的低血压，在较高剂量时可能导致大脑兴奋作用；然而，劳丹烷碱在人体中的效果尚未确定。

The degradation of cisatracurium is largely independent of liver metabolism. Cisatracurium undergoes Hofmann elimination (a pH and temperature-dependent chemical process) to form laudanosine and the monoquaternary acrylate metabolite. Non-specific plasma esterases hydrolyze the monoquaternary acrylate metabolite to form the monoquaternary alcohol metabolite (MQA). The MQA can also undergo Hofmann elimination, but the rate of this process is slower than the one detected for cisatracurium. Laudanosine is further metabolized to desmethyl metabolites that are conjugated with glucuronic acid and excreted in the urine. Laudanosine may cause transient hypotension and, in higher doses, cerebral excitatory effects when administered to several animal species; however, the effects of laudanosine in humans have not been established.

来源:DrugBank

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用概述：目前没有关于顺式阿曲库铵在哺乳期间使用的资料。由于它作用时间短、极性高且口服吸收不良，因此不太可能以高浓度进入母乳或进入婴儿的血液循环。当使用多种麻醉剂组合进行手术时，请遵循手术期间使用的问题最大的药物的建议。考虑使用不含苯甲醇防腐剂的顺式阿曲库铵产品。 ◉ 对哺乳婴儿的影响：截至修订日期，没有找到相关的已发布信息。 ◉ 对泌乳和母乳的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:No information is available on the use of cisatracurium during breastfeeding. Because it is short acting, highly polar and poorly absorbed orally, it is not likely to reach the breastmilk in high concentration or to reach the bloodstream of the infant. When a combination of anesthetic agents is used for a procedure, follow the recommendations for the most problematic medication used during the procedure. Consider using a cisatracurium product that has no benzyl alcohol preservative. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 蛋白质结合

顺阿曲库铵与血浆蛋白的结合尚未成功研究，因为其在生理pH下迅速降解。

The binding of cisatracurium to plasma proteins has not been successfully studied due to its rapid degradation at physiologic pH.

来源:DrugBank

吸收、分配和排泄

• 吸收

顺阿曲库铵的药代动力学遵循双室开放模型。顺阿曲库铵代谢为劳丹烷和单季铵醇代谢物（MQA）。在顺阿曲库铵静脉输注后，劳丹烷和MQA的Cmax分别是母化合物的6%和11%。与年轻患者相比，老年患者的顺阿曲库铵分布体积略大，这也导致更长的半衰期值。顺阿曲库铵的血浆清除率不受年龄影响。肝功能损害患者的分布体积和血浆清除率值略高；然而，这些微小的药代动力学差异在临床上并不被认为有显著意义。此外，终末期肾病患者顺阿曲库铵的药代动力学参数与健康成人患者相似。

The pharmacokinetics of cisatracurium follow a two-compartment open model. Cisatracurium is metabolized into laudanosine and monoquaternary alcohol metabolite (MQA). Following the IV infusion of cisatracurium, the Cmax of laudanosine and MQA were 6% and 11% of the parent compound, respectively. Compared to young patients, the volume of distribution of cisatracurium is slightly larger in elderly patients, which also leads to longer half-life values. The plasma clearance of cisatracurium was not affected by age. Patients with hepatic impairment have a slightly higher volume of distribution and plasma clearance values; however, these minor pharmacokinetic differences are not considered clinically significant. Additionally, the pharmacokinetic parameters of cisatracurium in patients with end-stage renal disease were similar to those detected in healthy adult patients.

来源:DrugBank

吸收、分配和排泄

• 消除途径

顺阿曲库铵的主要消除机制是霍夫曼消除，这是一种依赖于pH和温度的化学反应（大约占健康手术患者的80%）。肝脏和肾脏在顺阿曲库铵的消除中发挥较小作用（约20%）；然而，它们在顺阿曲库铵代谢物的代谢中扮演重要角色。在给予健康男性患者（n=6）¹⁴C-顺阿曲库铵的情况下，回收剂量中有4%在粪便中发现，95%在尿液中找到，大部分是结合型代谢物。不到10%的顺阿曲库铵剂量以未改变的专利药物形式被排泄。在另一组接受非放射性标记顺阿曲库铵（n=12）的导尿管手术管理的患者中，15%的顺阿曲库铵剂量以未改变的形式在尿液中排出。

The predominant elimination mechanism of cisatracurium is Hofmann elimination, a chemical process dependent on pH and temperature (approximately 80% in healthy surgical patients). The liver and kidney play a minor role in the elimination of cisatracurium (about 20%); however, they have a significant role in the metabolism of cisatracurium metabolites. In healthy male patients (n=6) given ¹⁴C-cisatracurium, 4% of the recovered dose was found in feces, and 95% was found in urine, mostly as conjugated metabolites. Less than 10% of the cisatracurium dose was excreted as the unchanged patent drug. In another group of patients with Foley catheters for surgical management given non-radiolabeled cisatracurium (n=12), 15% of the cisatracurium dose was excreted unchanged in urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

Cisatracurium的稳态分布容积为145 mL/kg。由于Cisatracurium besylate的分子量相对较大且极性较高，其分布容积较小。

Cisatracurium has a volume of distribution at steady state of 145 mL/kg. The volume of distribution of cisatracurium besylate is small due to its relatively large molecular weight and high polarity.

来源:DrugBank

吸收、分配和排泄

• 清除

西斯阿曲库铵的血浆清除率为4.57毫升/分钟/千克。

Cisatracurium has a plasma clearance of 4.57 mL/min/kg.

来源:DrugBank

文献信息

• PROCESS FOR THE RESOLUTION OF ISOQUINOLINE DERIVATIVES
  申请人：Segnalini Franca

  公开号：US20100298570A1

  公开（公告）日：2010-11-25

  A process for the resolution of racemic tetrahydropapaverine with optically active arylpropionic acids is described.

  描述了一种用光学活性芳基丙酸分离消旋四氢培烯的过程。
• PROCESS FOR PRODUCING CISATRACURIUM AND ASSOCIATED INTERMEDIATES
  申请人：Arad Oded

  公开号：US20100256381A1

  公开（公告）日：2010-10-07

  The present invention provides a process of producing cisatracurium compounds, e.g., cisatracurium besylate, from isoquinolinium salts of the structural formula (VIIA) wherein X − is an anion and R is H or a C 1 -C 6 alkyl, or an activated form of the carboxylic acid with 1,5-pentanediol to form a cisatracurium salt, optionally via an intermediate compound (VIII). The cisatracurium compounds can be purified using simple techniques to afford pure cisatracurium besylate without the need for HPLC purification.

  本发明提供了一种从(VIIA)结构式的异喹啉盐中生产顺-阿曲库铵化合物（例如顺-阿曲库铵苄甲酸盐）的方法，其中X-是阴离子，R是H或C1-C6烷基，或者是与1,5-戊二醇反应形成顺-阿曲库铵盐的羧酸的活化形式，可通过中间化合物(VIII)进行。可以使用简单的技术对顺-阿曲库铵化合物进行纯化，以获得不需要HPLC纯化的纯顺-阿曲库铵苄甲酸盐。
• Active agent delivery systems and methods for protecting and administering active agents
  申请人：Mickle Travis

  公开号：US20070232529A1

  公开（公告）日：2007-10-04

  The present invention relates to active agent delivery systems and more specifically to compositions that comprise amino acids, as single amino acids or peptides, covalently attached to active agents and methods for administering conjugated active agent compositions.

  本发明涉及活性物质输送系统，更具体地涉及包含氨基酸（作为单个氨基酸或肽）与活性物质共价连接的组合物以及用于给予共轭活性物质组合物的方法。
• (1R,1'R)-ATRACURIUM SALTS SEPARATION PROCESS
  申请人：Ostrovsky Elena

  公开号：US20100087650A1

  公开（公告）日：2010-04-08

  Provided is a method for separating cisatracurium from a mixture of atracurium isomers, which method includes eluting from a Reverse Phase (RP) stationary phase with a mobile phase in which the isomers are stable. The method of the present invention can be conveniently and inexpensively scaled up.
• (1R, 1'R)-ATRACURIUM SALTS SEPARATION PROCESS
  申请人：Arad Oded

  公开号：US20100099878A1

  公开（公告）日：2010-04-22

  The present invention provides an improved method of chromatographically separating the isomers of (1R,rR)-atracurium salts by high-performance liquid chromatography (HPLC), in the absence of a strong acid. The separation is preferably performed on a silica gel HPLC column using an eluent containing an organic solvent, a polar aprotic co-solvent and a weak organic acid.