(3S,6R,9R,12R,15R,18S,24S,30S,33R)-30-ethyl-33-[(E,1S)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone | 59865-13-3

• 物质功能分类: 生物化工 - 抑制剂 - 免疫抑制剂
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (3S,6R,9R,12R,15R,18S,24S,30S,33R)-30-ethyl-33-[(E,1S)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone
• CAS: 59865-13-3
• 化学式: C₆₂H₁₁₁N₁₁O₁₂
• 分子量: 1202.6
• InChiKey: PMATZTZNYRCHOR-WIUPBDCUSA-N

物化性质

• 熔点：
  148-151°C
• 比旋光度：
  D20 -244° (c = 0.6 in chloroform); D20 -189° (c = 0.5 in methanol)
• 沸点：
  838.63°C (rough estimate)
• 密度：
  0.9913 (rough estimate)
• 闪点：
  87℃
• 溶解度：
  乙醇：30 mg/mL
• 物理描述：
  Cyclosporin a appears as white prismatic needles (from acetone) or white powder. (NTP, 1992)
• 颜色/状态：
  Forms white prismatic crystals from acetone
• 旋光度：
  Optical rotation: -244 degrees @ 20 °C (c = 0.6 in chloroform), - 189 degrees @ 20 °C (c = 0.5 in methanol)
• 分解：
  When heated to decomposition it emits toxic fumes of /nitrogen oxides/.

计算性质

• 辛醇/水分配系数(LogP)：
  7.5
• 重原子数：
  85
• 可旋转键数：
  15
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  279
• 氢给体数：
  5
• 氢受体数：
  12

ADMET

代谢

环孢素在肝脏中被细胞色素P450 3A（CYP3A）酶系统广泛代谢，在一定程度上也会通过胃肠道和肾脏代谢。在人的胆汁、粪便、血液和尿液中已经鉴定出至少25种代谢物。尽管环孢素的环肽结构相对抵抗代谢，但其侧链被广泛代谢。所有的代谢物与母药相比，生物活性和毒性都降低了。

Cyclosporine is extensively metabolized in the liver by the cytochrome-P450 3A (CYP3A) enzyme system & to a lesser degree by the GI tract & kidneys. At least 25 metabolites have been identified in human bile, feces, blood, & urine. Although the cyclic peptide structure of cyclosporine is relatively resistant to metab, the side chains are extensively metabolized. All of the metabolites have both reduced biological activity & toxicity compared to the parent drug.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

在几项大型临床试验中，环孢素治疗的开始与血清胆红素水平的轻度升高有关，通常没有血清ALT或碱性磷酸酶的显著增加。血清酶的升高也有描述，但较少见。最近，这些并发症似乎较少发生，这可能是因为对环孢素的剂量和水平监测更为谨慎。此外，在治疗没有移植许多并发症的自身免疫疾病时，环孢素治疗与高达30%的患者出现轻度血清碱性磷酸酶升高有关，但异常是无症状的，通常是自限性的，很少需要调整剂量。在几个病例系列中，环孢素治疗也与胆泥和胆石症有关。有临床明显急性肝损伤的孤立病例报告归因于环孢素。发病时间是在开始使用环孢素后的几周内，血清酶升高的模式是胆汁淤积。一旦停止使用环孢素，恢复就会很快，尚未有因环孢素引起的慢性肝炎或急性肝衰竭的报道。

In several large clinical trials, initiation of cyclosporine therapy was associated with mild elevations in serum bilirubin levels, often without significant increases in serum ALT or alkaline phosphatase. Elevations in serum enzymes were also described, but less commonly. Recently, these complications appear to be less frequent, perhaps because of more careful dosing and monitoring of cyclosporine levels. Furthermore, in treatment of autoimmune diseases without the many complications of transplantation, cyclosporine therapy has been associated with mild serum alkaline phosphatase elevations in up to 30% of patients, but the abnormalities are asymptomatic, usually self-limiting and rarely require dose adjustment. In several case series, cyclosporine therapy has also been associated with biliary sludge and cholelithiasis. Isolated case reports of clinically apparent acute liver injury have been attributed to cyclosporine. The time to onset was within a few weeks of starting cyclosporine and the pattern of serum enzyme elevations was cholestatic. Recovery was prompt once cyclosporine was stopped and cases of chronic hepatitis or acute liver failure due to cyclosporine have not been reported.

来源:LiverTox

毒理性

• 肝毒性

在大规模随机对照试验中，使用伏环孢素的患者中，有3%的患者血清转氨酶水平短暂升高，但在接受传统治疗的对照组中，比率相似（2%）。与环孢素类似，伏环孢素治疗与碱性磷酸酶和胆红素水平的轻微增加有关，尽管这些值通常保持在正常范围内。在伏环孢素的上市前研究中，没有因治疗引起的临床上明显的肝损伤实例。然而，这种药物的临床经验有限，其他钙调神经磷酸酶抑制剂被发现偶尔会导致肝损伤，这些损伤通常是胆汁淤积性的，轻至中度严重，停止治疗后病程自限。

In large randomized controlled trials of voclosporin, serum aminotransferase levels were transiently elevated in 3% of patients, but rates were similar in controls receiving conventional therapy (2%). Similar to cyclosporine, voclosporin therapy is associated with minor increases in alkaline phosphatase and bilirubin levels, although values usually remain within the normal range. In the prelicensure studies of voclosporin, there were no instances of clinically apparent liver injury attributable to therapy. Clinical experience with this agent, however, has been limited and other calcineurin inhibitors have been found to cause rare instances of hepatic injury, which are generally cholestatic, mild-to-moderate in severity and self-limited in course once treatment is stopped.

来源:LiverTox

毒理性

• 致癌性证据

环孢菌素A：已知是一种人类致癌物。

Cyclosporin A: known to be a human carcinogen.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌物分类

国际癌症研究机构致癌物：环孢素

IARC Carcinogenic Agent:Cyclosporine

来源:International Agency for Research on Cancer (IARC)

毒理性

• 致癌物分类

国际癌症研究机构（IARC）致癌物分类：1类：对人类致癌

IARC Carcinogenic Classes:Group 1: Carcinogenic to humans

来源:International Agency for Research on Cancer (IARC)

吸收、分配和排泄

环孢素口服给药后，达到最高血药浓度的时间为1.5-2.0小时。与食物同服会延迟并减少吸收。在给药后30分钟内摄入高脂肪和低脂肪餐分别会使曲线下面积（AUC）减少约13%，最大浓度减少33%。这使得个体化门诊病人的剂量方案变得至关重要。环孢素在血管外分布广泛。静脉给药后，稳态分布体积在实体器官移植受者中据报道可高达3-5升/千克。仅有0.1%的环孢素以原形从尿液中排出。……环孢素及其代谢物主要通过胆汁进入粪便排出，仅有大约6%通过尿液排出。环孢素也通过人乳排出。

Following oral admin of cyclosporine, the time to peak blood concns is 1.5-2.0 hr. Admin with food both delays & decreases absorption. High & low fat meals consumed within 30 min of admin decr the AUC by approx 13% & the max concn by 33%. This makes it imperative to individualize dosage regimens for outpatients. Cyclosporine is distributed extensively outside the vascular compartment. After iv dosing, the steady-state volume of distribution has been reported to be as high as 3-5 liters/kg in solid-organ transplant recipients. Only 0.1% of cyclosporine is excreted unchanged in urine. ... Cyclosporine & its metabolites are excreted principally through the bile into the feces, with only approx 6% being excreted in the urine. Cyclosporine also is excreted in human milk.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

环孢素的吸收在口服给药后是不完全的。吸收的程度取决于包括个体患者和所用配方在内的几个变量。环孢素从血液中消除通常是双相的，终末半衰期为5-18小时。在肾移植成年受者中，静脉输注后的清除率大约为5-7毫升/分钟/千克，但结果会因年龄和患者群体而异。例如，心脏移植患者的清除速度较慢，而在儿童中较快。在治疗范围内，给药剂量与血浆浓度-时间曲线下面积之间的关系是线性的，但由于个体间变异性很大，因此需要个体监测。

... Absorption of cyclosporine is incomplete following oral admin. The extent of absorption depends upon several variables, including the individual patient & formulation used. The elimination of cyclosporine form the blood is generally biphasic, with a terminal half-life of 5-18 hr. After iv infusion, clearance is approx 5-7 ml/min/kg in adult recipients of renal transplants, but results differ by age & patient populations. For example, clearance is slower in cardiac transplant patients & more rapid in children. The relationship between admin dose & the area under the plasma concn-vs-time curve is linear within the therapeutic range, but the intersubject variability is so large that individual monitoring is required.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

临床医生可以在移植后的前几天通过持续静脉输液给予环孢素，然后在随后的时间里通过每日两次口服给药，以达到75-150 ng/ml的血浆环孢素浓度（通过高效液相色谱法测量），这相当于通过放射免疫分析法测量的全血环孢素浓度为300-600 ng/ml。保持大约75-150 ng/ml的血浆谷浓度似乎是安全的；然而，这并不一定保证免受肾毒性的影响。由于环孢素及其代谢物优先分布进入红细胞，血液水平通常高于血浆水平。当通过放射免疫分析法测得的血液环孢素水平为300-600 ng/ml时，脑脊液水平范围为10-50 ng/ml。10岁以下儿童的表观分布体积约为35 l/kg，成人为4.7 l/kg。

Clinicians can administer cyclosporine by continuous iv infusion during the first few days after transplantation, then orally by twice-daily doses, to achieve plasma cyclosporine concns (measured by HPLC) of 75-150 ng/ml (equivalent to whole blood cyclosporine concns of 300-600 ng/ml measured by radioimmunoassay). It appears safe to maintain a trough plasma cyclosporine concn of about 75-150 ng/ml; however, this does not necessarily guarantee safety from nephrotoxicity. Because of preferential distribution of cyclosporine & its metabolites into red blood cells, blood levels are generally higher than plasma levels. When blood cyclosporine levels are 300-600 ng/ml by radioimmunoassay, cerebrospinal fluid levels range from 10-50 ng/ml. The apparent volume of distribution in children under 10 yr of age is about 35 l/kg, & in adults, 4.7 l/kg.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

口服环孢素350毫克的消除半衰期是8.9小时；在1400毫克剂量后，半衰期是11.9小时。环孢素的消除主要是通过肝脏代谢形成18-25种代谢物。环孢素的代谢物几乎没有免疫抑制作用。环孢素在肝脏中通过细胞色素P450III氧化酶广泛代谢；然而，神经毒性和可能的肾毒性通常与环孢素代谢物血药水平升高有关。只有0.1%的剂量以原形排泄。

The elimination half-life of an oral cyclosporine dose of 350 mg is 8.9 hr; after a 1400 mg dose, the half-life is 11.9 hr. Elimination occurs predominantly by metab in the liver to form 18-25 metabolites. Metabolites of cyclosporine possess little immunosuppressive activity. Cyclosporine is extensively metabolized in the liver by cytochrome P450IIIA oxidase; however, neurotoxicity & possibly nephrotoxoicity usually correlate with raised blood levels of cyclosporine metabolites. Only 0.1% of a dose ix s excreted unchanged.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  T
• 安全说明：
  S22,S24/25,S36/37,S45,S53
• 危险类别码：
  R60,R22,R45
• WGK Germany：
  3
• 海关编码：
  2941909000
• 危险品运输编号：
  NONH for all modes of transport
• RTECS号：
  GZ4120000

制备方法与用途

根据提供的信息,以下是关于环孢素的主要内容总结:

化学性质:

• 白色针状结晶
• 溶于甲醇、乙醇、丙酮或乙醚,微溶于水
• [α]D20 -244°(C=0.6，氯仿)
• 急性毒性LD50: 小鼠107mg/kg, 大鼠2329mg/kg, 兔子>1000mg/kg

用途:

• 新型免疫抑制剂
• 抑制T细胞受体信号传导路径,用于分子生物学研究
• 临床用于肾移植、肝肺移植等器官移植
• 治疗自身免疫性疾病
• 对白血病、癌症、结核病有一定疗效
• 具有抗炎作用

副作用:

• 肾毒性:蛋白尿、管型尿等
• 肝毒性:高胆红素血症等
• 神经系统症状:小脑共济失调、感觉异常等
• 消化道反应:恶心呕吐等

生产方法: 以多孢木霉菌为生产菌株,经过发酵提取粗品,再纯化得到环孢素和环孢菌素C组分。

总结来说,环孢素是一种重要的免疫抑制剂,广泛应用于临床器官移植及自身免疫病治疗,但需要注意其潜在的毒副作用。