表阿霉素 | 56420-45-2

• 物质功能分类: 原料药 - 抗肿瘤药 - 抗生素类抗肿瘤药
• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 蒽环类药物
• 中文名称: 表阿霉素
• 中文别名: 表柔比星；表柔吡星；(8S,10S)-10-[(3"-氨基-2",3",6"-三脱氧-alpha-L-阿拉伯吡喃糖基)-O-]-6,8,11-；表比星
• 英文名称: Epirubicin
• 英文别名: 4'-epiadriamycin；(1S,3S)-3-glycoloyl-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-1-tetracenyl 3-amino-2,3,6-trideoxy-α-L-arabino-hexopyranoside；(7S,9S)-7-[(2R,4S,5R,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione；10-(4-amino-5-hydroxy-6-methyl-oxan-2-yl)oxy-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-9, 10-dihydro-7H-tetracene-5, 12-dione；doxorubixin hydrochloride；epirubicin hydrochloride
• CAS: 56420-45-2
• 化学式: C₂₇H₂₉NO₁₁
• 分子量: 543.527
• InChiKey: AOJJSUZBOXZQNB-VTZDEGQISA-N

物化性质

• 沸点：
  617.77°C (rough estimate)
• 密度：
  1.3783 (rough estimate)
• 溶解度：
  溶于二甲基亚砜
• 物理描述：
  Solid
• 熔点：
  344.53 °C
• 蒸汽压力：
  2.50X10-23 mm Hg at 25 °C (est)
• 稳定性/保质期：

  The stability of epirubicin in sodium chloride 0.9% injection, the degradation kinetics of an epirubicin 1 mg/ml solution and the stability of epirubicin 2 mg/ml in polypropylene syringes stored under hospital conditions were studied at various temperature. The degradation of epirubicin in sodium chloride 0.9% solutions followed first order kinetics. The shelf life was defined as the time by which the epirubicin concentration had decreased by 10% from the initial concentration. Epirubicin was stable in sodium chloride 0.9% injection stored in polypropylene containers for all time periods and all conditions. That resulted in a shelf life of at least 14 and 180 days at 25 °C and 4 °C, respectively. The maximum decrease in epirubicin concentration observed at 25 °C and 14 days was 4%, and at 4 °C and 180 days was 8%. The predicted shelf life obtained from Arrhenius equation was 72. and 3070 days at 25 and 4 °C, respectively, in both dark and illuminated conditions.

• 分解：
  When heated to decomposition it emits toxic fumes of /nitrogen oxides/.
• 解离常数：
  pKa1 = 9.17 (phenol); pKa2 = 9.93 (amine); pKa3 = 12.67 (hydroxyl) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  39
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  206
• 氢给体数：
  6
• 氢受体数：
  12

ADMET

代谢

在肝脏中广泛且迅速地代谢。表柔比星也可以被其他器官和细胞代谢，包括红细胞。四种主要的代谢途径是：(1) C-13酮基还原形成13(S)-二氢衍生物，表柔比星醇；(2) 未改变的药物和表柔比星醇与葡萄糖醛酸结合；(3) 通过水解过程失去氨基糖部分，形成多柔比星和多柔比星醇苷元；(4) 通过氧化还原过程失去氨基糖部分，形成7-脱氧多柔比星苷元和7-脱氧多柔比星醇苷元。表柔比星醇在体外表现出细胞毒性活性（约为表柔比星的10%），但它不太可能在体内达到产生细胞毒性的足够浓度。

Extensively and rapidly metabolized in the liver. Epirubicin is also metabolized by other organs and cells, including red blood cells. The four main metabolic routes are: (1) reduction of the C-13 keto-group with the formation of the 13(S)-dihydro derivative, epirubicinol; (2) conjugation of both the unchanged drug and epirubicinol with glucuronic acid; (3) loss of the amino sugar moiety through a hydrolytic process with the formation of the doxorubicin and doxorubicinol aglycones; and (4) loss of the amino sugar moiety through a redox process with the formation of the 7-deoxy-doxorubicin aglycone and 7-deoxy-doxorubicinol aglycone. Epirubicinol exhibits in vitro cytoxic activity (~10% that of epirubicin), but it is unlikely to reach sufficient concentrations in vivo to produce cytotoxic effects.

来源:DrugBank

代谢

表柔比星在肝脏中被广泛且迅速代谢，同时也被其他器官和细胞，包括红细胞代谢。已经确定了四种主要的代谢途径：(1) C-13位酮基还原形成13(S)-二氢衍生物，表柔比星醇；(2) 未改变的药物和表柔比星醇与葡萄糖醛酸结合；(3) 通过水解过程失去氨基糖部分，形成多柔比星和多柔比星醇的苷元；(4) 通过氧化还原过程失去氨基糖部分，形成7-脱氧多柔比星苷元和7-脱氧多柔比星醇苷元。表柔比星醇的体外细胞毒性活性是表柔比星的十分之一。由于表柔比星醇的血浆水平低于未改变的药物，它们不太可能达到体内产生细胞毒性的足够浓度。其他代谢物没有报告显著的活性或毒性。

Epirubicin is extensively and rapidly metabolized by the liver and is also metabolized by other organs and cells, including red blood cells. Four main metabolic routes have been identified: (1) reduction of the C-13 keto-group with the formation of the 13(S)-dihydro derivative, epirubicinol; (2) conjugation of both the unchanged drug and epirubicinol with glucuronic acid; (3) loss of the amino sugar moiety through a hydrolytic process with the formation of the doxorubicin and doxorubicinol aglycones; and (4) loss of the amino sugar moiety through a redox process with the formation of the 7-deoxy-doxorubicin aglycone and 7-deoxy-doxorubicinol aglycone. Epirubicinol has in vitro cytotoxic activity one-tenth that of epirubicin. As plasma levels of epirubicinol are lower than those of the unchanged drug, they are unlikely to reach in vivo concentrations sufficient for cytotoxicity. No significant activity or toxicity has been reported for the other metabolites.

来源:Hazardous Substances Data Bank (HSDB)

代谢

次级醇代谢物被认为是多柔比星（阿霉素，DOX）和其他抗癌蒽环类药物引起慢性心脏毒性的介质。在本研究中，添加了NADPH的人心胞质被发现可以还原多柔比星四环侧链上的羰基，产生次级醇代谢物多柔比星醇（DOXol）。当用表柔比星（EPI）替代多柔比星时，发现醇代谢物形成的水平降低，EPI是一种心脏毒性较低的光学异构体，特点是在与四环相连的氨基糖（道诺糖胺）的C-4位置上，羟基从轴向构型变为赤道构型。当用MEN替代多柔比星时，也观察到了类似的降低，MEN是一种新型蒽环类药物，具有减少心脏毒性的临床前证据。MEN的特点是四环上C-4位置缺少一个甲氧基团，并且在道诺糖胺和苷元之间插入了2,6-去氧-L-岩藻糖。与甲氧基或4-去甲氧基苷元以及许多单糖或二糖4-去甲氧基蒽环类药物的多重比较表明，缺乏甲氧基团和存在二糖单元都限制了MEN醇代谢物的形成。使用酶促生成的或纯化的蒽环类药物次级醇的研究还表明，存在二糖单元，而不是缺乏甲氧基团，使得MEN的代谢物与细胞质乌头酸酶的[4Fe-4S]簇反应性降低，这通过其被还原为母体羰基蒽环类药物的限量以及Fe(II)从簇中分散程度的降低得到证明。总的来说，这些研究（i）描述了甲氧基和糖取代基对蒽环类药物次级醇的形成和[4Fe-4S]反应性的不同影响，（ii）支持醇代谢物在蒽环类药物引起的心脏毒性中的作用，因为它们证明了心脏毒性较低的地塞米松和MEN 10755在形成这类代谢物的水平上有所降低，（iii）提示MEN的心脏毒性可能会通过其醇代谢物降低的[4Fe-4S]反应性进一步减少。

Secondary alcohol metabolites have been proposed to mediate chronic cardiotoxicity induced by doxorubicin (DOX) and other anticancer anthracyclines. In this study, NADPH-supplemented human cardiac cytosol was found to reduce the carbonyl group in the side chain of the tetracyclic ring of doxorubicin, producing the secondary alcohol metabolite doxorubicinol (DOXol). A decrease in the level of alcohol metabolite formation was observed by replacing doxorubicin with epirubicin (EPI), a less cardiotoxic analogue characterized by an axial-to-equatorial epimerization of the hydroxyl group at C-4 in the amino sugar bound to the tetracyclic ring (daunosamine). A similar decrease was observed by replacing doxorubicin with MEN, a novel anthracycline with preclinical evidence of reduced cardiotoxicity. MEN is characterized by the lack of a methoxy group at C-4 in the tetracyclic ring and by intercalation of 2, 6-dideoxy-L-fucose between daunosamine and the aglycone. Multiple comparisons with methoxy- or 4-demethoxyaglycones, and a number of mono- or disaccharide 4-demethoxyanthracyclines, showed that both the lack of the methoxy group and the presence of a disaccharide moiety limited alcohol metabolite formation by MEN. Studies with enzymatically generated or purified anthracycline secondary alcohols also showed that the presence of a disaccharide moiety, but not the lack of a methoxy group, made the metabolite of MEN less reactive with the [4Fe-4S] cluster of cytoplasmic aconitase, as evidenced by its limited reoxidation to the parent carbonyl anthracycline and by a reduced level of delocalization of Fe(II) from the cluster. Collectively, these studies (i) characterize the different influence of methoxy and sugar substituents on the formation and [4Fe-4S] reactivity of anthracycline secondary alcohols, (ii) lend support to the role of alcohol metabolites in anthracycline-induced cardiotoxicity, as they demonstrate that the less cardiotoxic EPI and MEN 10755 share a reduction in the level of formation of such metabolites, and (iii) suggest that the cardiotoxicity of MEN might be further decreased by the reduced [4Fe-4S] reactivity of its alcohol metabolite.

来源:Hazardous Substances Data Bank (HSDB)

代谢

许多抗癌药物被发现具有致癌性、致突变性和致畸性潜力。该研究的目的是对定期参与制备细胞毒剂物的医院药房人员进行细胞遗传学和内剂量监测，以测试在常规工作条件下由于职业暴露以及意外污染情况下可能的细胞毒素诱导的遗传毒性效应。...通过测量全血中的铂和血浆中的蒽环类药物来评估对细胞毒素的内部暴露。使用微核试验和姐妹染色单体交换分析在外周血淋巴细胞中确定细胞遗传损伤的水平。在2年的时间里进行了五轮监测。...在职业暴露受试者与对照组之间，姐妹染色单体交换（SCE）和微核（MN）的平均频率没有显著差异（9.9 +/- 1.4 对 10.1 +/- 1.2 SCEs/细胞和21.2 +/- 7.2 对 23.3 +/- 7.5 MN/2000双核细胞，n = 16）。在12起工作场所意外污染中有7起检测到SCE或MN的显著升高，而在这些受试者中没有观察到血液中铂和血浆中蒽环类的增加。通过测量血浆中的表柔比星，确定了两种未报告的污染情况。发现吸烟显著增加了SCE。个体SCE评分和MN评分之间没有观察到相关性。.../作者/的研究结果支持在意外污染情况下相关暴露于细胞毒素药物后SCE或MN的暂时性增加。医院药房人员与对照组之间SCE和MN没有显著差异，这指出了相应工作场所安全标准的高水平。

Many antineoplastic drugs were found to have carcinogenic, mutagenic and teratogenic potential. The aim of this study was to carry out cytogenetic and internal dose monitoring of hospital pharmacy personnel regularly involved in the preparation of cytostatic agents, in order to test possible cytostatics-induced genotoxic effects due to occupational exposure under routine working conditions, and in cases of accidental contamination. ... Platinum in whole blood and anthracyclines in plasma were measured to assess internal exposure to cytostatics. The level of cytogenetic damage was determined in peripheral blood lymphocytes with the micronucleus test and the sister chromatid exchange assay. Five series of monitoring were performed over a period of 2 years. ... No significant differences in the mean frequencies of sister chromatid exchanges (SCE) and micronuclei (MN) were found between occupationally exposed probands and controls (9.9 +/- 1.4 vs 10.1 +/- 1.2 SCEs/cell and 21.2 +/- 7.2 vs 23.3 +/- 7.5 MN/2000 binucleated (BN) cells, n = 16). Significant elevations of SCE or MN were detected in seven out of 12 cases of accidental contamination at the workplace, whereas no increase in platinum in blood and anthracyclines in plasma was observed in these probands. Two cases of non-reported contamination were identified by measurement of epirubicin in plasma. Smoking was found to increase the SCE significantly. No correlation between individual SCE scores and MN scores was observed. ... /The authors/ findings support a transient increase in SCE or MN after relevant exposure to cytostatic drugs in cases of accidental contamination. The lack of significant differences in SCE and MN between hospital pharmacy personnel and unexposed controls, points to high standards of safety at the corresponding workplaces.

来源:Hazardous Substances Data Bank (HSDB)

代谢

有令人信服的体外证据表明，仅基于血浆浓度的阿霉素或表阿霉素药代动力学评估可能无法完全阐明这两种药物之间的差异。这两种化合物都能与红细胞结合，它们与血红蛋白的不同结合可能会影响它们在体内的分布。本研究旨在比较阿霉素和表阿霉素的药代动力学和代谢，基于血浆浓度、与血细胞的关联量以及单次和多次注射后胆汁和尿液中未改变药物和代谢物的同步监测。心脏的肌浆网Ca2+ATP酶水平也被测量作为心脏毒性的生物标志物。雄性Sprague-Dawley大鼠以平行设计接受阿霉素或表阿霉素多次给药治疗（每周4 mg kg(-1)）或单次注射（20 mg kg(-1)）。在多次给药方案和单次注射后，定期收集血液、尿液和胆汁样本，在每个实验结束时取出心脏。测定血浆、血细胞、胆汁和尿液中每种药物的浓度，并根据区室分析同时对血浆和胆汁数据进行曲线拟合，估算药代动力学参数和常数。根据非区室分析分析血细胞相关药物的浓度。胆汁和尿液样本提供了体内的代谢数据。通过Western印迹测定的心脏中Ca2+ATP酶的水平被用作与动力学数据相关的毒效动力参数。多次给药方案减少了两种药物的总血浆清除率，并增加了血浆浓度-时间曲线下的面积。随着每周剂量的增加，与血细胞相关的阿霉素曲线下面积增加，相关的平均滞留时间（MRT）和表观分布体积（Vdss）稳步减少。与阿霉素相比，表阿霉素的平均滞留时间和Vdss显著增加。代谢数据表明，醇和苷元代谢物的水平存在显著差异。阿霉素醇和阿霉素苷元显著高于表阿霉素醇和表阿霉素苷元，而表阿霉素醇苷元高于阿霉素醇苷元。血细胞浓度-时间曲线下的面积与Ca2+ATP酶净强度的变化呈线性相关。本研究的结果表明，与血细胞相关的阿霉素和表阿霉素动力学的重要性。与血细胞相关的阿霉素曲线下面积减少与生物标志物净强度减少之间的线性相关性证实，这两种化合物之间的差异与它们与血细胞的相互作用有关。这一观察结果以及观察到的代谢差异可能强调了血细胞在阿霉素和表阿霉素分布和代谢中的重要作用。

There is compelling in-vitro evidence that the evaluation of doxorubicin or epirubicin pharmacokinetics based solely on plasma concentration may not fully elucidate the differences between the two drugs. Both compounds bind to erythrocytes and their different binding to hemoglobin may influence their disposition in the body. The purpose of the present study was to compare the pharmacokinetics and metabolism of doxorubicin and epirubicin based on the plasma concentration, amount associated with blood cells and simultaneous monitoring of biliary and urinary elimination of unchanged drug and metabolites after single- and multiple-dose injections. The level of sarcoplasmic reticulum Ca2+ATPase in the heart was also measured as a biomarker of cardiotoxicity. Male Sprague-Dawley rats were treated in a parallel design with doxorubicin or epirubicin on a multiple-dosing basis (4 mg kg(-1) per week) or as a single dose injection (20 mg kg(-1)). Blood, urine and bile samples were collected periodically after each dose in the multiple-dosing regimen and the single dose injection, and at the end of each experiment the hearts were removed. The concentrations of each drug in plasma, blood cells, bile and urine samples were determined, and by simultaneous curve-fitting of plasma and bile data according to compartmental analysis, the pharmacokinetic parameters and constants were estimated. The concentration of drug associated with blood cells was analyzed according to non-compartmental analysis. The bile and urine samples provided the in-vivo metabolic data. The level of Ca2+ATPase in the heart, determined by Western blotting, was used as the toxicodynamic parameterto correlate with the kinetic data. Multiple-dosing regimens reduced the total plasma clearance and increased the area under the plasma concentration-time curve of both drugs. Also, the area under the curve of doxorubicin associated with blood cells increased with the weekly doses, and the related mean residence time (MRT) and apparent volume of distribution (Vdss) were steadily reduced. In contrast to doxorubicin, the mean residence time and Vdss of epirubicin increased significantly. Metabolic data indicated significant differences in the level of alcohol and aglycones metabolites. Doxorubicinol and doxorubicin aglycones were significantly greater than epirubicinol and epirubicin aglycone, whereas epirubicinol aglycone was greater than doxorubicinol aglycone. The area under the blood cells concentration-time curve correlated linearly with the changes in Ca2+ATPase net intensity. The results of this study demonstrate the importance of the kinetics of epirubicin and doxorubicin associated with blood cells. Linear correlation between the reduction of net intensity of the biomarker with the area under the curve of doxorubicin associated with blood cells confirms that the differences between the two compounds are related to their interaction with blood cells. This observation together with the observed differences in metabolism may underline a significant role for blood cells in distribution and metabolism of doxorubicin and epirubicin.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：表柔比星是红橙色的结晶，被配制成静脉给药的溶液。它被用作辅助治疗的一部分，在原发性乳腺癌切除后，用于腋窝淋巴结肿瘤侵犯的患者。人类暴露和毒性：已经报道了高于推荐剂量的给药情况，剂量范围从150到250毫克/平方米。在这些患者中观察到的有害事件与表柔比星已知的毒性定性相似。大多数患者在适当的支持性治疗下恢复。继发性急性髓细胞性白血病（AML）已经在使用蒽环类药物治疗的乳腺癌患者中报道，包括表柔比星。心脏毒性，包括致命的充血性心力衰竭（CHF），可能会在表柔比星治疗期间或治疗终止后数月至数年内发生。表柔比星在体外（人淋巴细胞染色体畸变）存在和不存在代谢激活的情况下都是致裂变剂。动物研究：为了评估表柔比星的致癌潜力，没有进行传统的长期动物研究，但是将3.6毫克/千克的单一剂量的表柔比星静脉注射给雌性大鼠，观察到1年内乳腺肿瘤（主要是纤维腺瘤）的发生率大约增加了一倍。每3周静脉注射0.5毫克/千克表柔比星给大鼠，共十次剂量，在18个月的观察期间增加了雄性大鼠皮下纤维瘤的发生率。此外，给新生大鼠在出生后第一天和第十天每天皮下注射0.75或1.0毫克/千克，共注射四次，在24个月的观察期间，与对照组相比，增加了有肿瘤的动物的发生率。在妊娠的第5到15天，每天静脉注射0.8毫克/千克表柔比星给大鼠，对胚胎有毒（增加吸收和着床后损失）并导致胎儿生长迟缓（体重减轻），但在此剂量下没有致畸性。在妊娠的第9和第10天，每天静脉注射2毫克/千克表柔比星给大鼠，对胚胎有毒（增加晚期吸收、着床后损失和死胎；减少活胎），减缓胎儿生长（体重减轻）并导致胎盘重量减少。这个剂量也是致畸的，引起了许多外部（肛门闭锁、尾巴变形、异常生殖结节）、内脏（主要是胃肠道、泌尿和心血管系统）和骨骼（长骨和腰带变形、肋骨异常、不规则脊椎骨化）的畸形。在妊娠的第6到18天，每天静脉注射最多0.2毫克/千克表柔比星给兔，没有胚胎毒性或致畸性，但是0.32毫克/千克的母体毒性剂量增加了流产和延迟骨化。在妊娠的第10到12天，每天静脉注射1毫克/千克的母体毒性剂量的表柔比星给兔，引起了流产，但没有观察到其他胚胎胎儿毒性或致畸性的迹象。当从妊娠第17天到分娩后第21天每天给大鼠母体注射最多0.5毫克/千克表柔比星时，没有观察到对后代发育、功能活动、行为或生殖性能的永久性变化。在鼠的生育研究中，雄性每天给药9周，并与在交配前2周和妊娠第7天每天给药的雌性交配。当两性每天给予0.3毫克/千克的剂量时，没有怀孕发生。在0.1毫克/千克/天剂量下没有观察到交配行为或生育的影响，但是雄性大鼠出现了睾丸和附睾萎缩以及减精子生成。0.1毫克/千克/天的剂量也引起了胚胎致死性。在这些研究中，在0.03毫克/千克/天剂量下观察到胎儿生长迟缓的发生率增加。兔和狗每天多次给药表柔比星也引起了雄性生殖器官的萎缩。单次20.5和12毫克/千克剂量的静脉注射表柔比星分别引起了小鼠和大鼠的睾丸萎缩。16.7毫克/千克的单次剂量的表柔比星引起了大鼠子宫萎缩。表柔比星在体外对细菌（AMes试验）在存在或不存在代谢激活的情况下都是致突变剂，对哺乳动物细胞（中国仓鼠肺纤维细胞V79的HGPRT试验）在不存在但存在代谢激活的情况下是致突变剂。表柔比星在体内（小鼠骨髓染色体畸变）是致裂变剂。

IDENTIFICATION AND USE: Epirubicin is red-orange crystals that are formulated into a solution for intravenous administration. It is used as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer. HUMAN EXPOSURE AND TOXICITY: Instances of administration of doses higher than recommended have been reported at doses ranging from 150 to 250 mg/sq m. The observed adverse events in these patients were qualitatively similar to known toxicities of epirubicin. Most of the patients recovered with appropriate supportive care. Secondary acute myelogenous leukemia (AML) has been reported in patients with breast cancer treated with anthracyclines, including epirubicin. Cardiac toxicity, including fatal congestive heart failure (CHF), may occur either during therapy with epirubicin or months to years after termination of therapy. Epirubicin was clastogenic in vitro (chromosome aberrations in human lymphocytes) both in the presence and absence of metabolic activation. ANIMAL STUDIES: Conventional long-term animal studies to evaluate the carcinogenic potential of epirubicin have not been conducted, but intravenous administration of a single 3.6 mg/kg epirubicin dose to female rats approximately doubled the incidence of mammary tumors (primarily fibroadenomas) observed at 1 year. Administration of 0.5 mg/kg epirubicin intravenously to rats every 3 weeks for ten doses increased the incidence of subcutaneous fibromas in males over an 18-month observation period. In addition, subcutaneous administration of 0.75 or 1.0 mg/kg/day to newborn rats for 4 days on both the first and tenth day after birth for a total of eight doses increased the incidence of animals with tumors compared to controls during a 24-month observation period. Administration of 0.8 mg/kg/day intravenously of epirubicin to rats during days 5 to 15 of gestation was embryotoxic (increased resorptions and post-implantation loss) and caused fetal growth retardation (decreased body weight), but was not teratogenic up to this dose. Administration of 2 mg/kg/day intravenously of epirubicin to rats on days 9 and 10 of gestation was embryotoxic (increased late resorptions, post-implantation losses, and dead fetuses; and decreased live fetuses), retarded fetal growth (decreased body weight), and caused decreased placental weight. This dose was also teratogenic, causing numerous external (anal atresia, misshapen tail, abnormal genital tubercle), visceral (primarily gastrointestinal, urinary, and cardiovascular systems), and skeletal (deformed long bones and girdles, rib abnormalities, irregular spinal ossification) malformations. Administration of intravenous epirubicin to rabbits at doses up to 0.2 mg/kg/day during days 6 to 18 of gestation was not embryotoxic or teratogenic, but a maternally toxic dose of 0.32 mg/kg/day increased abortions and delayed ossification. Administration of a maternally toxic intravenous dose of 1 mg/kg/day epirubicin to rabbits on days 10 to 12 of gestation induced abortion, but no other signs of embryofetal toxicity or teratogenicity were observed. When doses up to 0.5 mg/kg/day epirubicin were administered to rat dams from day 17 of gestation to day 21 after delivery, no permanent changes were observed in the development, functional activity, behavior, or reproductive performance of the offspring. In fertility studies in rats, males were given epirubicin daily for 9 weeks and mated with females that were given epirubicin daily for 2 weeks prior to mating and through day 7 of gestation. When dose of 0.3 mg/kg/day was administered to both sexes, no pregnancies resulted. No effects on mating behavior or fertility were observed at 0.1 mg/kg/day, but male rats had atrophy of the testes and epididymis, and reduced spermatogenesis. The 0.1 mg/kg/day dose also caused embryolethality. An increased incidence of fetal growth retardation was observed in these studies at 0.03 mg/kg/day. Multiple daily doses of epirubicin to rabbits and dogs also caused atrophy of male reproductive organs. Single 20.5 and 12 mg/kg doses of intravenous epirubicin caused testicular atrophy in mice and rats, respectively. A single dose of 16.7 mg/kg epirubicin caused uterine atrophy in rats. Epirubicin was mutagenic in vitro to bacteria (Ames test) either in the presence or absence of metabolic activation and to mammalian cells (HGPRT assay in V79 Chinese hamster lung fibroblasts) in the absence but not in the presence of metabolic activation. Epirubicin was clastogenic in vivo (chromosome aberration in mouse bone marrow).

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

表柔比星具有抗有丝分裂和细胞毒性活性。它通过多种提出的机制抑制核酸（DNA和RNA）和蛋白质的合成：表柔比星通过与碱基对之间的嵌入形成DNA复合物，并且通过稳定DNA-拓扑异构酶II复合物来抑制拓扑异构酶II的活性，阻止拓扑异构酶II催化的连接-再连接反应的再连接部分。它还通过抑制DNA解旋酶活性来干扰DNA复制和转录。

Epirubicin has antimitotic and cytotoxic activity. It inhibits nucleic acid (DNA and RNA) and protein synthesis through a number of proposed mechanisms of action: Epirubicin forms complexes with DNA by intercalation between base pairs, and it inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes. It also interferes with DNA replication and transcription by inhibiting DNA helicase activity.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 药物性肝损伤

化合物：表柔比星

Compound:epirubicin

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI标注：模糊的DILI关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重程度等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

百分之百

100%

来源:DrugBank

吸收、分配和排泄

• 消除途径

表柔比星及其主要代谢物通过胆汁排泄消除，其次通过尿液排泄。

Epirubicin and its major metabolites are eliminated through biliary excretion and, to a lesser extent, by urinary excretion.

来源:DrugBank

吸收、分配和排泄

• 分布容积

21 ± 2 L/kg [60 mg/m2 剂量] 27 ± 11 L/kg [75 mg/m2 剂量] 23 ± 7 L/kg [120 mg/m2 剂量] 21 ± 7 L/kg [150 mg/m2 剂量]

21 ± 2 L/kg [60 mg/m2 Dose] 27 ± 11 L/kg [75 mg/m2 Dose] 23 ± 7 L/kg [120 mg/m2 Dose] 21 ± 7 L/kg [150 mg/m2 Dose]

来源:DrugBank

吸收、分配和排泄

• 清除

65 +/- 8 L/小时 [接受静脉注射表柔比星 60 mg/m2 的实体瘤患者] 83 +/- 14 L/小时 [接受静脉注射表柔比星 75 mg/m2 的实体瘤患者] 65 +/- 13 L/小时 [接受静脉注射表柔比星 120 mg/m2 的实体瘤患者] 69 +/- 13 L/小时 [接受静脉注射表柔比星 150 mg/m2 的实体瘤患者]

65 +/- 8 L/hour [Patients1 with Solid Tumors Receiving Intravenous Epirubicin 60 mg/m2] 83 +/- 14 L/hour [Patients1 with Solid Tumors Receiving Intravenous Epirubicin 75 mg/m2] 65 +/- 13 L/hour [Patients1 with Solid Tumors Receiving Intravenous Epirubicin 120 mg/m2] 69 +/- 13 L/hour [Patients1 with Solid Tumors Receiving Intravenous Epirubicin 150 mg/m2]

来源:DrugBank

吸收、分配和排泄

...研究了/蒽环类抗生素/多柔比星（1）、4'表多柔比星（表柔比星；II）和柔红霉素（道诺霉素；III）在患者体内的血浆和组织分布。通过液相色谱法测定了I和II及其13-羟基代谢物的血浆水平，以及III的血浆水平。得出结论，这3种药物的血浆动力学相似，I和II的组织摄取几乎相同。肿瘤组织对药物的浓缩程度最高，而脂肪组织的浓度最低。

... The plasma and tissue distribution of /anthracyline antibiotics/ doxorubicin (1), 4' epidoxorubicin (epirubicin; II) and daunorubicin (daunomycin; III) were studied in patients. Plasma levels of I and II and their 13 hydroxy metabolites were determined by LC, as were plasma levels of III. It was concluded that plasma kinetics for the 3 drugs were similar, and that tissue uptake for I and II were virtually the same. Tumor tissue concentrated the drugs to the greatest extent, while adipose tissue had the lowest concentrations.

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

**药理作用**

• 用于治疗多种癌症：乳腺癌、卵巢癌、消化道癌（如晚期胃癌、晚期直肠结肠癌）、恶性淋巴瘤、肺癌及恶性黑色素瘤等。

• 常见不良反应：骨髓抑制，主要表现为白细胞、血小板减少；心脏毒性较阿霉素低，可能引起心律失常和ST-T段改变；胃肠道反应有恶心、呕吐、腹泻等。

**药代动力学**

• 肝脏代谢快，主要通过胆道排出。
• 血浆消除半衰期约为30～40小时。

<img src="图1：表阿霉素的结构式">

**注意事项与相互作用**

1. 避免与其他药物共用注射器给药；
2. 不能与肝素混合以免沉淀；
3. 药物溶解后应在室温下保存，避免阳光直射，且不宜久存。

• 禁忌症：孕妇禁用。
• 使用方法：不可口服或肌注、鞘内给药；最好通过输液管冲入以减少组织损伤风险。
• 存储条件：药物应在4～10℃下保存，避免阳光直射。
  

**化学性质**

盐酸表柔比星（Epirubicin Hydrochloride）：C27H31NO11?HCI，橘红色结晶，熔点约185°C。溶液应避光保存。

• 制备方法

通过特定步骤合成表阿霉素，包括酰化、氧化还原等化学反应。

用途: 葸 <|im_STart|>assiSTant

表阿霉素的药理作用与相关特性 药理作用

• 用于治疗多种癌症

  • 乳腺癌
  • 卵巢癌
  • 消化道癌（如晚期胃癌、晚期直肠结肠癌）
  • 恶性淋巴瘤
  • 肺癌
  • 恶性黑色素瘤

• 常见不良反应

  • 骨髓抑制：表现为白细胞和血小板减少，但通常较轻。
  • 心脏毒性：较低，主要为心律失常和ST-T段改变，一般可自行恢复。累积剂量超过1000mg/m²时，可能出现慢性心肌病变。
  • 胃肠道反应：恶心、呕吐、腹泻等，发生率低于阿霉素。

• 其他不良反应

  • 毛发脱落
  • 皮肤色素沉着
  • 发热
  • 乏力
  • 皮炎

药代动力学

• 代谢与排泄：在体内较快被代谢，主要通过肝脏代谢并经胆道排出。
• 半衰期：血浆消除半衰期约为30～40小时。
• 清除率：血浆清除率为约0.9～1.14L/min。

结构与性质

• 化学名称与分子式

  • 盐酸表柔比星（Epirubicin Hydrochloride）：C₂₇H₂₉NO₁₁·HCI，橘红色结晶，熔点约185℃。

• 物理特性

  • [α]²₀⁺ = +274°(C=0.01, 甲醇)
  • 溶液应避光保存。

制备方法

通过特定步骤合成表阿霉素，包括：

1. 化合物(I)经三氟乙酸酐N-酰化，以对氨基进行保护，得到化合物（Ⅱ）。
2. 再氧化为酮(Ⅲ)，然后还原为醇(Ⅳ)。
3. 在酸作用下去除醚键，再经三氟乙酸酐酯化为化合物(Ⅵ)。
4. 然后进行选择性氯代，得到所需的侧链(VII)。
5. 化合物(Ⅷ)经二甲缩丙酮反应成缩酮(Ⅸ)，然后和上述制得的侧链(Ⅶ)反应，最终通过水解得到表阿霉素。

使用注意事项与药物相互作用

1. 避免与其他药物共用注射器给药。
2. 不能与肝素混合以免沉淀。
3. 与氨茶碱接触可使溶液变成蓝色。
4. 不能与皮质激素类同时滴注。
5. 与头孢菌素类接触可引起沉淀。
6. 不能与碱性药物或溶液长期接触。
7. 与其他蒽环类抗生素如多柔比星（阿霉素）存在交叉反应，需谨慎使用。
8. 避免与某些含金属离子的药物同时使用。

禁忌症

• 孕妇禁用

使用方法与存储条件

1. 不可口服或肌注、鞘内给药。
2. 最好通过输液管冲入以减少组织损伤风险。
3. 药物应在4～10℃下保存，避免阳光直射。

以上是关于表阿霉素的主要药理作用、化学性质及制备方法的详细说明。确保在临床使用时遵循专业指导和注意事项。

上下游信息

反应信息

• 作为反应物：
  描述：

  表阿霉素 在 palladium 10% on activated carbon 、 氢气 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三甲胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 23.0h， 生成
  参考文献：
  名称：

  MULTI-TARGETED UBENIMEX PRODRUG DERIVATIVE AND PREPARATION METHOD AND USE THEREOF

  摘要：

  公开号：

  EP2947070B1
• 作为产物：
  描述：

  (8S,10S)-10-((2R,4S,5R,6S)-4-Amino-5-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy)-8-(1,2-dihydroxy-ethyl)-6,8,11-trihydroxy-1-methoxy-7,8,9,10-tetrahydro-naphthacene-5,12-dione 在 sodium tetrahydroborate 作用下， 生成 表阿霉素
  参考文献：
  名称：

  Impairment of myocardial contractility by anticancer anthracyclines: role of secondary alcohol metabolites and evidence of reduced toxicity by a novel disaccharide analogue

  摘要：

  蒽环类抗癌药物多柔比星（DOX）会导致心肌毒性。其侧链羰基通过酶促还原作用转化为次级醇代谢物，而该代谢物被认为与心脏毒性相关。因此，我们监测了暴露于DOX或两种生成较少次级醇代谢物的类似物（表柔比星EPI和新型二糖基蒽环类化合物MEN 10755）的雄性大鼠右心室条的负性变时作用（定义为对舒张后收缩的抑制作用）。 30μM EPI的摄取率高于DOX，但由于其对羰基还原具有抗性，导致形成相同数量的醇代谢物。MEN 10755表现出摄取受损，因此形成了最低水平的醇代谢物。相应地，DOX和EPI抑制了舒张后收缩约40–50%，而MEN 10755抑制了约6%。 100μM EPI表现出与DOX相等的摄取率，但形成了约50%的醇代谢物减少。100μM MEN 10755仍然表现出最低摄取率，并形成了较EPI约60%的醇代谢物减少。在这些条件下，DOX对舒张后收缩的抑制作用为88%。EPI和MEN 10755的抑制作用分别为DOX的约18%（P<0.05）和约80%（P<0.001）。 30–100μM DOX、EPI或MEN 10755的负性变时作用与细胞中醇代谢物的水平（r=0.88，P<0.0001）和羰基蒽环类药物的水平（r=0.79，P<0.0001）相关。然而，多重比较显示，醇代谢物在抑制收缩性方面的效果比羰基蒽环类药物高出约20–40倍。因此，通过化学手段（如侧链缬氨酸酯化）增加MEN 10755的摄取和转化为醇代谢物（而不是保留为羰基形式），可以增强其负性变时作用。 这些结果表明，次级醇代谢物是心脏毒性的关键介导因素。减少摄取并限制向醇代谢物转化的形成，可能会使MEN 10755比DOX和EPI更具心脏耐受性。 英国药理学杂志 (2001) 134, 1271–1278; doi:10.1038/sj.bjp.0704369

  DOI：

  10.1038/sj.bjp.0704369
• 作为试剂：
  描述：

  溴 、 表阿霉素 在 表柔比星EP杂质F 、 表阿霉素 作用下， 生成 表柔比星EP杂质F
  参考文献：
  名称：

  Genetically modified strains producing anthracycline metabolites useful as cancer drugs

  摘要：

  该发明涉及一种微生物菌株，其在发酵液中至少以0.5g/l的滴定度产生蒽环素代谢物。

  公开号：

  US20100143977A1

文献信息

• [EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
  申请人：GILEAD APOLLO LLC

  公开号：WO2017075056A1

  公开（公告）日：2017-05-04

  The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

  本发明提供了化合物I和II，这些化合物可用作乙酰辅酶A羧化酶（ACC）的抑制剂，以及它们的组合物和使用方法。
• [EN] COMPOUNDS AND COMPOSITIONS COMPRISING CDK INHIBITORS AND METHODS FOR THE TREATMENT OF CANCER<br/>[FR] COMPOSÉS ET COMPOSITIONS COMPRENANT DES INHIBITEURS DES CDK ET MÉTHODES DE TRAITEMENT DU CANCER
  申请人：UNIV GEORGIA STATE RES FOUND

  公开号：WO2010129858A1

  公开（公告）日：2010-11-11

  Disclosed herein are compounds suitable for use as antitumor agents, methods for treating cancer wherein the disclosed compounds are used in making a medicament for the treatment of cancer, methods for treating a tumor comprising, administering to a subject a composition comprising one or more of the disclosed cytotoxic agents, and methods for preparing the disclosed antitumor agents.

  本文披露了适用作抗肿瘤药剂的化合物，用于治疗癌症的方法，其中所披露的化合物用于制备治疗癌症的药物，治疗肿瘤的方法包括向受试者施用包含一种或多种所披露的细胞毒性药剂的组合物，以及制备所披露的抗肿瘤药剂的方法。
• Cobalamin conjugates for anti-tumor therapy
  申请人：Weinshenker M. Ned

  公开号：US20050054607A1

  公开（公告）日：2005-03-10

  The present invention provides a cobalamin-drug conjugate suitable for the treatment of tumor related diseases. Cobalamin is indirectly covalently bound to an anti-tumor drug via a cleavable linker and one or more optional spacers. Cobalamin is covalently bound to a first spacer or the cleavable linker via the 5′-OH of the cobalamin ribose ring. The drug is bound to a second spacer of the cleavable linker via an existing or added functional group on the drug. After administration, the conjugate forms a complex with transcobalamin (any of its isoforms). The complex then binds to a receptor on a cell membrane and is taken up into the cell. Once in the cell, an intracellular enzyme cleaves the conjugate thereby releasing the drug. Depending upon the structure of the conjugate, a particular class or type of intracellular enzyme affects the cleavage. Due to the high demand for cobalamin in growing cells, tumor cells typically take up a higher percentage of the conjugate than do normal non-growing cells. The conjugate of the invention advantageously provides a reduced systemic toxicity and enhanced efficacy as compared to a corresponding free drug.

  本发明提供了一种适用于治疗肿瘤相关疾病的钴胺素-药物结合物。钴胺素通过可切割的连接剂间接共价结合到抗肿瘤药物上，还可以通过一个或多个可选的间隔物。钴胺素通过其核糖环的5'-OH与第一间隔物或可切割连接剂共价结合。药物通过其现有或添加的功能基团与可切割连接剂的第二间隔物结合。在给药后，结合物与转钴胺素（其任何同工异构体）形成复合物。然后，该复合物结合到细胞膜上的受体并被细胞摄取。一旦进入细胞，细胞内酶将切割结合物，从而释放药物。根据结合物的结构，特定类别或类型的细胞内酶影响切割。由于生长细胞对钴胺素的需求量较高，肿瘤细胞通常摄取结合物的比例高于正常非生长细胞。本发明的结合物与相应的游离药物相比，具有较低的全身毒性和增强的疗效。
• [EN] 2-QUINOLONE DERIVED INHIBITORS OF BCL6<br/>[FR] INHIBITEURS DE BCL6 DÉRIVÉS DE 2-QUINOLONE
  申请人：CANCER RESEARCH TECH LTD

  公开号：WO2018215798A1

  公开（公告）日：2018-11-29

  The present invention relates to compounds of formula I that function as inhibitors of BCL6(B- cell lymphoma 6) activity: Formula I wherein X1, X2, X3, R1, R2, R3, R4 and R5 are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer,as well as other diseases or conditions in which BCL6 activity is implicated.

  本发明涉及作为BCL6（B细胞淋巴瘤6）活性抑制剂的I式化合物：式中X1、X2、X3、R1、R2、R3、R4和R5分别如本文所定义。本发明还涉及制备这些化合物的方法，包括含有它们的药物组合物，以及它们在治疗增生性疾病（如癌症）以及其他BCL6活性所涉及的疾病或病况中的用途。
• [EN] INHIBITORS OF BRUTON'S TYROSINE KINASE<br/>[FR] INHIBITEURS DE TYROSINE KINASE DE BRUTON
  申请人：BIOCAD JOINT STOCK CO

  公开号：WO2018092047A1

  公开（公告）日：2018-05-24

  The present invention relates to a new compound of formula I: or pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: V1 is C or N, V2 is C(R2) or N, whereby if V1 is C then V2 is N, if V1 is C then V2 is C(R2), or if V1 is N then V2 is C(R2); each n, k is independently 0, 1; each R2, R11 is independently H, D, Hal, CN, NR'R", C(O)NR'R", C1-C6 alkoxy; R3 is H, D, hydroxy, C(O)C1-C6 alkyl, C(O)C2-C6 alkenyl, C(O)C2-C6 alkynyl, C1-C6 alkyl; R4 is H, Hal, CN, CONR'R", hydroxy, C1-C6 alkyl, C1-C6 alkoxy; L is CH2, NH, O or chemical bond; R1 is selected from the group of the fragments, comprising: Fragment 1, Fragment 2, Fragment 3 each A1, A2, A3, A4 is independently CH, N, CHal; each A5, A6, A7, A8, A9 is independently C, CH or N; R5 is H, CN, Hal, CONR'R", C1-C6 alkyl, non-substituted or substituted by one or more halogens; each R' and R" is independently selected from the group, comprising H, C1-C6 alkyl, C1-C6 cycloalkyl, aryl; R6 is selected from the group: [formula II] each R7, R8, R9, R10 is independently vinyl, methylacetylenyl; Hal is CI, Br, I, F, which have properties of inhibitor of Bruton's tyrosine kinase (Btk), to pharmaceutical compositions containing such compounds, and their use as pharmaceuticals for treatment of diseases and disorder.

  本发明涉及一种新的化合物，其化学式为I：或其药学上可接受的盐、溶剂化合物或立体异构体，其中：V1为C或N，V2为C(R2)或N，如果V1为C，则V2为N，如果V1为C，则V2为C(R2)，或者如果V1为N，则V2为C(R2)；每个n，k独立地为0或1；每个R2，R11独立地为H，D，Hal，CN，NR'R"，C(O)NR'R"，C1-C6烷氧基；R3为H，D，羟基，C(O)C1-C6烷基，C(O)C2-C6烯基，C(O)C2-C6炔基，C1-C6烷基；R4为H，Hal，CN，CONR'R"，羟基，C1-C6烷基，C1-C6烷氧基；L为CH2，NH，O或化学键；R1从包括的片段组中选择：片段1，片段2，片段3，每个A1，A2，A3，A4独立地为CH，N，CHal；每个A5，A6，A7，A8，A9独立地为C，CH或N；R5为H，CN，Hal，CONR'R"，C1-C6烷基，未取代或被一个或多个卤素取代；每个R'和R"独立地从包括H，C1-C6烷基，C1-C6环烷基，芳基的组中选择；R6从组中选择：[化学式II]每个R7，R8，R9，R10独立地为乙烯基，甲基乙炔基；Hal为CI，Br，I，F，具有布鲁顿酪氨酸激酶（Btk）抑制剂的性质，以及含有这种化合物的药物组合物，以及它们作为治疗疾病和紊乱的药物的用途。

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