(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,30S,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-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 | 159351-69-6

• 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
• 英文名称: (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,30S,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-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: 159351-69-6
• 化学式: C₅₃H₈₃NO₁₄
• 分子量: 958.2
• InChiKey: HKVAMNSJSFKALM-FESMRNBOSA-N

物化性质

• 熔点：
  NA
• 沸点：
  998.7±75.0 °C(Predicted)
• 密度：
  1.18±0.1 g/cm3(Predicted)
• 闪点：
  2℃
• 溶解度：
  可溶于DMSO（高达100mg/ml）或乙醇（高达100mg/ml）。
• 稳定性/保质期：

  Stable under recommended storage conditions.

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  68
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  205
• 氢给体数：
  3
• 氢受体数：
  14

ADMET

代谢

依维莫司是CYP3A4和PgP的底物。口服给药后，依维莫司是人类血液中的主要循环成分。已经在人类血液中检测到依维莫司的六种主要代谢物，包括三种单羟基化代谢物，两种水解开环产物，以及一种依维莫司的磷脂酰胆碱共价结合物。这些代谢物也在毒性研究中使用的动物种类中被识别，并且显示出比依维莫司本身大约低100倍的活动性。

Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100-times less activity than everolimus itself.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

血清酶水平升高发生在多达四分之一的服用依维莫司的患者中，但这些异常通常是轻微的、无症状的，并且是自限性的，很少需要调整剂量或停药。肝功能测试升高超过上限五倍的情况只发生在1%到2%的治疗患者中。相比之下，尽管依维莫司在多种恶性和非恶性综合征中广泛使用，但特异质、临床上明显的急性肝损伤并未与依维莫司治疗相关联。血清酶、胆红素升高和肝炎在依维莫司的产品标签中被列为潜在的副作用。因此，由于依维莫司导致的临床上明显的急性肝损伤并伴有黄疸的情况可能非常罕见，甚至可能根本不会发生。 重要的是，依维莫司具有免疫抑制作用，在接受癌症治疗的患者中，已与乙型肝炎病毒再激活的发作相关联，这可能是严重的，甚至可能是致命的。反向血清转换（在预先存在乙型肝炎抗体的人中发展HBsAg，无论是抗-HBs还是抗-HBc）也已有报道。 可能性评分：E*（未证实的，也不太可能是临床上明显肝损伤的原因，但能够诱导乙型肝炎病毒的再激活）。

Serum enzyme elevations occur in up to a quarter of patients taking everolimus, but the abnormalities are usually mild, asymptomatic and self-limiting, rarely requiring dose modification or discontinuation. Liver test elevations above 5 times ULN occur in only 1% to 2% of treated patients. In contrast, idiosyncratic, clinically apparent acute liver injury has not been linked to everolimus therapy despite its wide scale use in several malignant and non-malignant syndromes. Elevations in serum enzymes and bilirubin and hepatitis are listed as potential adverse events in the product label for everolimun. Thus, acute clinically apparent liver injury with jaundice due to everolimus is probably quite rare, if it occurs at all. Importantly, everolimus is immunosuppressive and therapy in patients with cancer has been associated with episodes of reactivation of hepatitis B, which can be severe and even fatal. Reverse seroconversion (development of HBsAg in a person with preexisting antibody to hepatitis B, either anti-HBs or anti-HBc) has also been reported. Likelihood score: E* (unproven and also unlikely cause of clinically apparent liver injury but capable of inducing reactivation of hepatitis B).

来源:LiverTox

毒理性

• 相互作用

使用HMG-CoA还原酶抑制剂（如洛伐他汀或辛伐他汀）在肾移植患者中进行的依维莫司与环孢素的临床试验中强烈不推荐，因为HMG-CoA还原酶抑制剂与环孢素之间存在相互作用。Zortress的制造商建议，在接受依维莫司和环孢素治疗的同时正在接受HMG-CoA还原酶抑制剂和/或纤维酸衍生物的患者中，应监测可能发生的横纹肌溶解症和其他不良反应，这些不良反应在这些降脂药物的使用说明中有描述。

Use of HMG-CoA reductase inhibitors such as lovastatin or simvastatin was strongly discouraged in clinical trials of everolimus with cyclosporine in renal transplant patients because of an interaction between HMG-CoA reductase inhibitors and cyclosporine. The manufacturer of Zortress recommends that patients receiving everolimus and cyclosporine therapy who are concurrently receiving an HMG-CoA reductase inhibitor and/or fibric acid derivative be monitored for the possible development of rhabdomyolysis and other adverse effects, which are described in the prescribing information for these antilipemic agents.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在健康个体中进行的研究表明，单次剂量的依维莫司与阿托伐他汀（CYP3A4底物）或普伐他汀（非CYP3A4底物和P-糖蛋白底物）之间没有临床重要的药代动力学相互作用；血浆中HMG-CoA还原酶的生物活性也没有受到显著影响。因此，当依维莫司与阿托伐他汀或普伐他汀同时使用时，不需要调整剂量。在一项群体药代动力学分析中，辛伐他汀（CYP3A4底物）并未影响依维莫司的清除率。Zortress的生产商警告，这些结果不能推广到其他HMG-CoA还原酶抑制剂。

Studies in healthy individuals indicate that there are no clinically important pharmacokinetic interactions between single-dose everolimus and atorvastatin (a CYP3A4 substrate) or pravastatin (a non-CYP3A4 substrate and P-gp substrate); HMG-CoA reductase bioactivity in plasma also was not substantially affected. Therefore, dosage adjustments are not necessary when everolimus and atorvastatin or pravastatin are used concurrently. In a population pharmacokinetic analysis, simvastatin (a CYP3A4 substrate) did not affect clearance of everolimus. The manufacturer of Zortress cautions that these results cannot be extrapolated to other HMG-CoA reductase inhibitors.