30-ethyl-33-[(E,1S,2S)-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 - 肽模拟物
• 英文名称: 30-ethyl-33-[(E,1S,2S)-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-WCIOLWJGSA-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。尽管环孢素的环状肽结构相对抵抗代谢，但其侧链被广泛代谢。所有代谢物与母药相比，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

• 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)

毒理性

• 致癌物分类

国际癌症研究机构专论集：第50卷：（1990年）药物

IARC Monographs:Volume 50: (1990) Pharmaceutical Drugs

来源:International Agency for Research on Cancer (IARC)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用概要：环孢霉素的浓度在不同的案例报告和系列中变化很大。这种可变性似乎部分是由于报告中采样时间的不一致，可能与采样时乳汁的脂肪含量有关。在典型的母体环孢霉素血药水平下，完全母乳喂养的婴儿通常不会接受超过母亲体重调整剂量的约2%，或者是儿科移植维持剂量的2%，并且通常低于1%。在大多数母乳喂养的婴儿中，血液中检测不到环孢霉素；然而，偶尔婴儿的血液中会有可检测到的水平，即使乳汁水平和婴儿剂量看起来很低。 许多婴儿在母亲使用环孢霉素期间被母乳喂养，通常同时使用皮质类固醇，有时还同时使用硫唑嘌呤。至少有两位母亲在成功母乳喂养第一个婴儿后，又成功母乳喂养了第二个婴儿。没有关于对婴儿生长、发育或肾脏功能产生不良影响的报告，尽管并没有总是进行或报告彻底的随访检查。美国和欧洲的专家指南、国家移植妊娠登记处和其他专家认为在母乳喂养期间使用环孢霉素可能是安全的，尽管其他人表达了关切。如果在此期间使用该药物，应监测母乳喂养的婴儿，可能包括测量血清水平以排除毒性。 由于眼部吸收有限，预期眼用环孢霉素不会对母乳喂养的婴儿产生任何不良影响。为了在滴眼后大幅减少到达母乳中的药物量，应在眼角处对泪点施加压力1分钟或更长时间，然后用吸收性纸巾去除多余的溶液。 ◉ 对母乳喂养婴儿的影响：一名婴儿被母乳喂养，随访显示婴儿保持健康和正常。 一名母亲每天两次服用3毫克/公斤的环孢霉素，完全母乳喂养她的婴儿直到断奶，部分母乳喂养持续到14个月。婴儿的肾脏功能稳定，两岁时健康。这位母亲还用同样的药物治疗母乳喂养了第二个婴儿。 在7名婴儿中，母亲在服用环孢霉素和泼尼松（其中6名还同时服用硫唑嘌呤）期间进行了4到12个月的母乳喂养，婴儿的肾功能未受影响，他们正常生长。 一名母亲在服用环孢霉素、硫唑嘌呤和泼尼松期间部分母乳喂养她的婴儿。没有报告随访数据。 一名婴儿在母亲每天两次服用环孢霉素300毫克、硫唑嘌呤和泼尼松期间，完全母乳喂养了10.5个月。部分母乳喂养持续了2年。婴儿在12个月时生长正常。这位母亲还用同样的药物方案母乳喂养了第二个孩子。 四名婴儿在母亲使用环孢霉素期间被母乳喂养。其中三人随访时临床上未发现不良影响，其中一人血清肌酐和尿素氮（BUN）测量正常。第四个婴儿没有报告随访。 报告了两名母亲服用环孢霉素并母乳喂养的婴儿的案例。其中一名母亲每天服用环孢霉素200毫克以及硫唑嘌呤、泼尼松、地尔硫卓和叶酸。第二名母亲每天服用环孢霉素120毫克以及甲基多巴、泼尼松和钙三醇。两位母亲最初完全母乳喂养她们的婴儿，并分别持续了5个月和14个月。据报道，婴儿身体健康，肾功能正常。 一名孕妇在怀孕26周时因重度溃疡性结肠炎开始每天服用环孢霉素5毫克/公斤，并在母乳喂养期间继续服用。她广泛地母乳喂养她的婴儿，3个月大时婴儿健康。 国家移植妊娠登记处报告了1991年至2011年间收集的母亲在器官移植后母乳喂养婴儿的数据。共有43位移植母亲（主要是肾脏移植）在母乳喂养总共49名婴儿期间使用了环孢霉素。哺乳期从1周到2年不等，对儿童的随访时间从几周到16年不等。一名婴儿出现了轻度血小板计数升高和与年龄不符的异常白蛋白/球蛋白比率；16个月时，实验室数值正常。其余婴儿或儿童没有问题报告。截至2013年12月，共有43位母亲母乳喂养了55名婴儿，最长24个月，婴儿没有出现明显的不良影响。 一名妇女每天服用环孢霉素200毫克治疗银屑病，同时完全母乳喂养她的婴儿6个月。12个月大时，婴儿发育正常，没有明显的不良影响。 一名患有肾病综合征的妇女在怀孕和哺乳期间服用了环孢霉素、泼尼松和羟基氯喹。在母乳喂养期间，她每天早晨服用环孢霉素125毫克，晚上服用100毫克（总计每天3毫克/公斤），羟基氯喹200毫克和泼尼松30毫克。她的双胞胎婴儿在出生后第7天开始部分母乳喂养（70到80%的母乳），她继续母乳喂养了几个月。婴儿在一个月时体重正常增长，在出生后三个月内没有不良反应。 ◉ 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。<|user|>

◉ Summary of Use during Lactation:Cyclosporine levels vary considerably in several case reports and series. This variability seems to be partially due to inconsistent sampling times among the reports and probably related to the fat content of the milk at the time of sampling. With typical maternal cyclosporine blood levels, a completely breastfed infant would usually receive no more than about 2% of the mother's weight-adjusted dosage or pediatric transplantation maintenance dosage, and often less than 1%. In most breastfed infants, cyclosporine is not detectable in blood; however, occasionally infants have had detectable blood levels, even when milk levels and infant dosage were apparently low. Numerous infants have been breastfed during maternal cyclosporine use, usually with a concurrent corticosteroid and sometimes with concurrent azathioprine. At least 2 mothers successfully breastfed a second infant after successfully breastfeeding the first infant. No reports of adverse effects on infants’ growth, development or kidney function have been reported, although thorough follow-up examinations have not always been performed or reported. United States and European expert guidelines, the National Transplantation Pregnancy Registry and other experts consider cyclosporine to be probably safe to use during breastfeeding, although others have expressed concern.Breastfed infants should be monitored if this drug is used during lactation, possibly including measurement of serum levels to rule out toxicity if there is a concern. Because absorption from the eye is limited, ophthalmic cyclosporine would not be expected to cause any adverse effects in breastfed infants. To substantially diminish the amount of drug that reaches the breastmilk after using eye drops, place pressure over the tear duct by the corner of the eye for 1 minute or more, then remove the excess solution with an absorbent tissue. ◉ Effects in Breastfed Infants:One infant was breastfed and follow-up showed that the infant remained healthy and normal. A mother who was taking cyclosporine 3 mg/kg twice daily completely breastfed her infant until weaning with partial breastfeeding until 14 months. The infant's kidney function was stable and she was healthy at 2 years of age. This mother also breastfed a second infant. In 7 infants breastfed for 4 to 12 months during maternal cyclosporine and prednisolone (plus azathioprine in 6 of the 7), infant renal function was unaffected, and they grew normally. One mother partially breastfed her infant during cyclosporine, azathioprine and prednisone use. No follow-up data were reported. One infant was exclusively breastfed for 10.5 months during maternal use of cyclosporine 300 mg twice daily, azathioprine and prednisone. Partial breastfeeding continued for 2 years. The infant thrived with normal growth at 12 months. The mother also breastfed a second child while on the same drug regimen. Four infants breastfed during maternal cyclosporine use. In three, no adverse effects were noted clinically on follow-up and one of these had normal serum creatinine and urea nitrogen (BUN) measured. No follow-up was reported on the fourth infant. Two cases were reported of infants whose mothers were taking cyclosporine and breastfeeding. One mother was taking cyclosporine 200 mg daily as well as azathioprine, prednisone, diltiazem, and folate. The second mother was taking cyclosporine 120 mg daily as well as methyldopa, prednisone, and calcitriol. Both mothers exclusively breastfed their infants initially and continued for 5 and 14 months, respectively. The infants were reportedly healthy and had normal renal function. A woman with severe ulcerative colitis during pregnancy received cyclosporine 5 mg/kg daily from 26 weeks of pregnancy and continued while breastfeeding. She extensive breastfed her infant and at 3 months of age the infant was healthy. The National Transplantation Pregnancy Registry reported data gathered from 1991 to 2011 on mothers who breastfed their infants following organ transplantation. A total of 43 mothers with transplants (mostly kidney) used cyclosporine while breastfeeding a total of 49 infants. Duration of nursing ranged from 1 week to 2 years and follow-up of the children ranged from weeks to 16 years. One infant experienced mildly elevated platelet count and an abnormal albumin/globulin ratio for age; at 16 months, laboratory values were normal. There were no reports of problems in the remainder of the infants or children. As of December 2013, a total of 43 mothers had breastfed 55 infants for as long as 24 months with no apparent adverse effects in infants. A woman took cyclosporine 200 mg daily for psoriasis while exclusively breastfeeding her infant for 6 months. At 12 months of age, the infant was developing normally and had no discernible adverse effects from the drug in milk. A woman with nephrotic syndrome took cyclosporine, prednisone, and hydroxychloroquine during pregnancy and lactation. While breastfeeding she took cyclosporine 125 mg in the morning and 100 mg at night (total of 3 mg/kg daily), hydroxychloroquine 200 mg daily and prednisone 30 mg daily. Her twin infants began partially breastfeeding (70 to 80% breastmilk) on day 7 postpartum and she continued to breastfeed for several months. The infants gained weight normally at one month of age and had no adverse reactions in the first three months postpartum. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

吸收、分配和排泄

在口服环孢素后，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%，使最高浓度减少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。在静脉给药后，稳态分布容积在实体器官移植受者中可高达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，只有大约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别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，但个体间的变异性很大，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，然后通过每天两次的口服剂量，以达到血浆环孢素浓度（通过高效液相色谱法测量）为75-150 ng/ml（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）。维持大约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危害。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量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。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。环孢素在肝脏中被细胞色素P450IIIA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相关。只有0.1%的剂量以原形排出。

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。