2-amino-4,6-dimethyl-3-oxo-1-N,9-N-bis[(3S,6S,7R,10S,16S)-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-3,10-di(propan-2-yl)-8-oxa-1,4,11,14-tetrazabicyclo[14.3.0]nonadecan-6-yl]phenoxazine-1,9-dicarboxamide

• 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: 2-amino-4,6-dimethyl-3-oxo-1-N,9-N-bis[(3S,6S,7R,10S,16S)-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-3,10-di(propan-2-yl)-8-oxa-1,4,11,14-tetrazabicyclo[14.3.0]nonadecan-6-yl]phenoxazine-1,9-dicarboxamide
• 化学式: C₆₂H₈₆N₁₂O₁₆
• 分子量: 1255.4
• InChiKey: RJURFGZVJUQBHK-DCUCITLNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  90
• 可旋转键数：
  8
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  356
• 氢给体数：
  5
• 氢受体数：
  18

ADMET

代谢

达克替康似乎只有轻微代谢；在尿液中检测到了少量药物的单内酯。

Dactinomycin appears to be only slightly metabolized; small amounts of monolactones of the drug have been detected in the urine.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

多柔比星与其他药物联合化疗与血清酶升高有关，升高的比例因剂量、其他联合使用的药物以及监测频率和定义升高的标准而异。ALT升高通常是无症状和短暂的，可能会在无需调整剂量的情况下自行解决。在许多情况下，由于接触其他可能具有肝毒性的药物，很难将肝功能测试异常归因于多柔比星。 多柔比星还可能引起一种被称为肝病-血小板减少症综合征（HTS）的独特形式的临床明显肝损伤，这种综合征可能是严重的，甚至致命的。这种综合征似乎是由于窦状隙阻塞，但也可能存在直接肝和骨髓损伤的成分。在大规模研究中，接受包括多柔比星方案治疗的癌症儿童中，有1%到5%的儿童出现了急性肝损伤和提示HTS的血小板减少症。这种综合征在年龄较小的儿童和高剂量的多柔比星治疗中更为常见。发病时间通常在首次给药后3到6周内，往往在多柔比星周期性化疗的第2或第3个疗程后的5到10天内出现。症状的发作通常是突然的，儿童典型表现为右上腹疼痛或压痛、肝肿大、肝功能测试异常和过度出血的迹象，如鼻出血或瘀伤。血清转氨酶水平在病程早期显著升高（高于正常上限的10到100倍），但迅速下降，7到14天内可能恢复正常。血小板计数通常低于25,000/μL，也会迅速恢复。血清碱性磷酸酶通常正常，胆红素水平仅轻微升高，除非病程进展并导致死亡。血清氨和INR也可能升高，急性综合征期间常常发展成腹水。损伤的整体模式类似于急性肝细胞坏死，肝脏组织学显示中央小叶坏死和窦状隙阻塞的证据。恢复通常是快速和完全的。 可能性评分：C（可能是临床明显肝损伤的原因）。

Chemotherapy with dactinomycin in combination with other agents is associated with serum enzyme elevations in a high, but variable proportion of patients depending upon the dose, other agents used as well as the frequency of monitoring and criteria used to define elevations. The ALT elevations are usually asymptomatic and transient and may resolve without dose modification. In many instances, it is difficult to attribute the liver test abnormalities to dactinomycin, because of the exposure to other potentially hepatotoxic agents. Dactinomycin can also cause a distinctive form of clinically apparent liver injury referred to as hepatopathy-thrombocytopenia syndrome (HTS) that can be severe and even fatal. This syndrome appears to be due to sinusoidal obstruction, but there may also be an element of direct hepatic and bone marrow injury. In large studies, between 1% and 5% of children with cancer treated with regimens including dactinomycin developed acute hepatic injury and thrombocytopenia suggestive of HTS. The syndrome is more common in younger children and with higher doses of dactinomycin. The time to onset is typically within 3 to 6 weeks after the initial dose, often arising 5 to 10 days after the 2nd or 3rd course of cyclic chemotherapy with dactinomycin. The onset of symptoms is sudden, and children characteristically present with right upper quadrant pain or tenderness, hepatomegaly, liver test abnormalities and signs of excessive bleeding such as epistaxis or bruising. Serum aminotransferase levels are markedly elevated (10 to 100 times ULN) early in the course, but fall rapidly and can be normal within 7 to 14 days. The platelet count is generally less than 25,000/μL and also resolves rapidly. Serum alkaline phosphatase is typically normal and bilirubin levels are minimally elevated, except if the course is progressive and fatal. Serum ammonia and INR may also be raised, and ascites often develops during the acute syndrome. The overall pattern of injury resembles acute hepatic necrosis, and liver histology shows centrolobular necrosis and evidence of sinusoidal obstruction. Recovery is rapid and usually complete. Likelihood score: C (Probable cause of clinically apparent liver injury).

来源:LiverTox

毒理性

• 致癌性证据

人类致癌性证据不足。动物致癌性证据有限。总体评估：第3组：该物质对人类致癌性无法分类。

Inadequate evidence of carcinogenicity in humans. Limited evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans.

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剂：放线菌素D

IARC Carcinogenic Agent:Actinomycin D

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：第3组：无法归类其对人类致癌性

IARC Carcinogenic Classes:Group 3: Not classifiable as to its carcinogenicity 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著：第10卷：（1976年）一些天然存在的物质

IARC Monographs:Volume 10: (1976) Some Naturally Occurring Substances

来源:International Agency for Research on Cancer (IARC)

吸收、分配和排泄

链霉素从胃肠道吸收不良。该药物对组织极为刺激，因此必须静脉给药。

Dactinomycin is poorly absorbed from the GI tract. The drug is extremely irritating to tissues and, therefore, must be administered iv.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

放线菌素D迅速分布到组织中，在骨髓和带核细胞（包括粒细胞和淋巴细胞）中浓度较高。该药物似乎很难穿越血脑屏障，或者根本不能穿越。

Dactinomycin is rapidly distributed into tissues, with high concentrations in bone marrow and nucleated cells, including granulocytes and lymphocytes. The drug appears to cross the blood-brain barrier poorly, if at all.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

“血浆蛋白结合/达克替尼霉素/为5%。”

Plasma protein binding /of dactinomycin/ is 5%.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

显然，放线菌素D会穿过胎盘。目前尚不清楚放线菌素D是否会分布到乳汁中。

Dactinomycin apparently crosses the placenta. It is not known if dactinomycin is distributed into milk.

来源:Hazardous Substances Data Bank (HSDB)