雷帕霉素 | 53123-88-9

• 物质功能分类: 原料药 - 影响免疫功能药 - 免疫抑制药
• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酯内酰胺
• 中文名称: 雷帕霉素
• 中文别名: 西罗莫司
• 英文名称: sirolimus
• 英文别名: Rapamycin；Rapa；(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone；rapamune；RAP；(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-3-methoxycyclohexyl]-1-methyl-ethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][ 1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone；temsirolimus；HY-10219；CCI-779；(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone
• CAS: 53123-88-9
• 化学式: C₅₁H₇₉NO₁₃
• 分子量: 914.187
• InChiKey: QFJCIRLUMZQUOT-HPLJOQBZSA-N

物化性质

• 熔点：
  183-185°C
• 比旋光度：
  D25 -58.2° (methanol)
• 沸点：
  799.83°C (rough estimate)
• 密度：
  1.0352 (rough estimate)
• 闪点：
  87 °C
• 溶解度：
  乙醇：可溶2MM
• 物理描述：
  Solid
• 颜色/状态：
  Colorless crystalline solid from ether
• 旋光度：
  Specific optical rotation at 25 °C for D (sodium) line = -58.2 deg (methanol)
• 碰撞截面：
  311.6 Ų [M+Na]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]
• 稳定性/保质期：

  如果按照规定使用和储存，则不会发生分解，并且尚未发现有任何已知的危险反应。

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  65
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  195
• 氢给体数：
  3
• 氢受体数：
  13

ADMET

代谢

西罗莫司在小肠壁和肝脏中经历广泛的代谢。西罗莫司主要通过CYP3A4的O-脱甲基化和/或羟基化反应，形成七种主要代谢物，包括羟基、脱甲基和羟基脱甲基代谢物，这些代谢物在药理学上是不活跃的。西罗莫司还从小肠上皮细胞逆向转运到肠道腔中。

Sirolimus undergoes extensive metabolism in the intestinal wall and liver. Sirolimus is primarily metabolized by O-demethylation and/or hydroxylation via CYP3A4 to form seven major metabolites, including hydroxy, demethyl, and hydroxydemethyl metabolites, which are pharmacologically inactive. Sirolimus also undergoes counter-transport from enterocytes of the small intestine into the gut lumen.

来源:DrugBank

代谢

西罗莫司是细胞色素P450 IIIA4（CYP3A4）和P-糖蛋白的底物。西罗莫司通过O-去甲基化 和/或 羟基化被广泛代谢。在全血中可以识别出七种主要代谢物，包括羟基化、去甲基化和羟基去甲基化代谢物。其中一些代谢物也可以在血浆、粪便和尿液样本中检测到。葡萄糖醛酸和硫酸结合物在任何生物基质中都不存在。

Sirolimus is a substrate for both cytochrome P450 IIIA4 (CYP3A4) and P-glycoprotein. Sirolimus is extensively metabolized by O-demethylation and/or hydroxylation. Seven major metabolites, including hydroxy, demethyl, and hydroxydemethyl, are identifiable in whole blood. Some of these metabolites are also detectable in plasma, fecal, and urine samples. Glucuronide and sulfate conjugates are not present in any of the biologic matrices.

来源:Hazardous Substances Data Bank (HSDB)

代谢

生物转化：肝脏广泛转化，通过细胞色素P450 3A酶。主要代谢物包括羟基西罗莫司、去甲基西罗莫司和羟基去甲基西罗莫司。

Biotransformation: Hepatic, extensive, by cytochrome p450 3A enzymes. Major metabolites include hydroxysirolimus, demethylsirolimus, and hydroxydemethyl-sirolimus.

来源:Hazardous Substances Data Bank (HSDB)

代谢

... 在将西罗莫司与人和猪的小肠微体一起孵化后，使用高效液相色谱/电喷雾-质谱法检测到了五种代谢物：羟基、二羟基、三羟基、去甲基和二去甲基西罗莫司。同样的代谢物也由人肝微体和猪小肠粘膜在Ussing室中产生。抗-CYP3A抗体以及特定的CYP3A抑制剂脱罗兰霉素和红霉素抑制了西罗莫司在小肠的代谢，确认了与肝脏中一样，CYP3A酶负责小肠中西罗莫司的代谢。...

... After incubation of sirolimus with human and pig small intestinal microsomes, five metabolites were detected using high performance liquid chromatography/electrospray-mass spectrometry: hydroxy, dihydroxy, trihydroxy, desmethyl and didesmethyl sirolimus. The same metabolites were generated by human liver microsomes and pig small intestinal mucosa in the Ussing chamber. Anti-CYP3A antibodies, as well as the specific CYP3A inhibitors troleandomycin and erythromycin, inhibited small intestinal metabolism of sirolimus, confirming that, as in the liver, CYP3A enzymes are responsible for sirolimus metabolism in the small intestine. ...

来源:Hazardous Substances Data Bank (HSDB)

代谢

西罗莫司已知的人类代谢物包括39-O-去甲基西罗莫司、24-羟基西罗莫司、12-羟基西罗莫司、11-羟基西罗莫司、16-O-去甲基西罗莫司、46-羟基西罗莫司和25-羟基西罗莫司。

Sirolimus has known human metabolites that include 39-O-Desmethylsirolimus, 24-Hydroxy-sirolimus, 12-Hydroxy-sirolimus, 11-Hydroxy-sirolimus, 16-O-Desmethylsirolimus, 46-Hydroxy-sirolimus, and 25-Hydroxy-sirolimus.

来源:NORMAN Suspect List Exchange

毒理性

• 肝毒性

西罗莫司治疗的患者中有一部分会出现血清酶升高，但异常通常是轻微的、无症状的，并且是自限性的，很少需要调整剂量或停药。有报道称西罗莫司使用过程中出现了罕见的胆汁淤积性肝炎，但由此剂引起的临床上明显的肝损伤的临床特征尚未被很好地定义。�