amphotericin B

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: amphotericin B
• 英文别名: (1R,3S,5R,6R,9R,11R,15S,16R,17R,18S,19E,21E,23E,25E,27E,29E,31E,33R,36R,37S)-33-[(2R,3S,4S,5S,6R)-4-amino-3,5-dihydroxy-6-methyloxan-2-yl]oxy-1,3,5,6,9,11,17,37-octahydroxy-15,16,18-trimethyl-13-oxo-14,39-dioxabicyclo[33.3.1]nonatriaconta-19,21,23,25,27,29,31-heptaene-36-carboxylic acid
• 化学式: C₄₇H₇₃NO₁₇
• 分子量: 924.093
• InChiKey: APKFDSVGJQXUKY-ZCGADPMASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  65
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.66
• 拓扑面积：
  320
• 氢给体数：
  12
• 氢受体数：
  18

ADMET

毒理性

• 肝毒性

多达20%的使用两性霉素的患者会出现轻度和短暂的肝酶升高。临床上明显的肝毒性很少见，但已经发表了一些令人信服的病例。肝脏损伤最早可能在开始治疗后的4到14天出现，通常表现为肝细胞型或混合型的酶升高。大多数患者没有症状或黄疸。停止治疗后会迅速恢复。此外，尽管罕见但已有报告在开始使用两性霉素后的几天内出现显著的孤立性高胆红素血症，升高的主要是直接（结合）胆红素部分。这些患者会出现肉眼可见的黄疸，但没有全身症状，血清ALT或碱性磷酸酶水平几乎没有升高，也没有明显的肝脏损伤证据。最后，已有报告在接收两性霉素的患者中出现了罕见的急性胆汁淤积性肝炎并伴有黄疸，但这些患者通常病情危重，并且接触了多种可能具有肝毒性的药物，因此将病因归咎于两性霉素的依据较弱。

Mild and transient elevations in liver enzymes occur in up to 20% of patients receiving amphotericin. Clinically apparent hepatotoxicity is rare, but several convincing cases have been published. The liver injury arises as early as 4 to 14 days after starting therapy, typically with a hepatocellular or mixed pattern of enzyme elevation. Most patients have no symptoms or jaundice. Recovery occurs promptly upon stopping therapy. In addition, isolated but dramatic instances of hyperbilirubinemia arising within days of starting amphotericin have been reported with elevations largely in the direct (conjugated) bilirubin fraction. These patients become visually jaundiced but have no constitutional symptoms, minimal if any elevations in serum ALT or alkaline phosphatase levels, and no evidence of frank hepatic injury. Finally, rare instances of acute cholestatic hepatitis with jaundice have been reported in patients receiving amphotericin, but these patients have generally been critically ill and exposed to multiple potentially hepatotoxic agents, so that the attribution to amphotericin has been weak.

来源:LiverTox

毒理性

• 相互作用

由于肾毒性作用可能具有相加性，应尽可能避免同时或连续使用两性霉素B和其他具有类似毒性潜力的药物（例如，氨基糖苷类抗生素、卡泊霉素、可利霉素、顺铂、环孢素、甲氧氟烷、戊烷脒、多粘菌素B、万古霉素）。

Since nephrotoxic effects may be additive, the concurrent or sequential use of amphotericin B and other drugs with similar toxic potentials (eg, aminoglycosides, capreomycin, colistill, cisplatin, cyclosporine, methoxyflurane, pentamidine, polymyxin B, vancomycin) should be avoided, if possible.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

据报道，皮质类固醇可能会增强两性霉素B引起的钾流失，除非有必要控制对两性霉素B的不良反应，否则不应同时使用。

Corticosteroids reportedly may enhance the potassium depletion caused by amphotericin B and should not be used concomitantly unless necessary to control adverse reactions to amphotericin B.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

抗肿瘤药物（例如，美克洛塞）可能会增强接受两性霉素B治疗的患者出现肾毒性、支气管痉挛和低血压的风险，因此应非常谨慎地使用此类联合治疗。

Antineoplastic agents (eg, mechlorethamine) may enhance the potential for renal toxicity, bronchospasm, and hypotension in patients receiving amphotericin B and such concomitant therapy should be used only with great caution.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在一项随机双盲研究中，评估了常规静脉注射两性霉素B和两性霉素B胆固醇硫酸盐复合物在发热中性粒细胞减少症患者中的使用情况，这些患者的基线血清肌酐浓度正常。研究中，肾脏毒性（定义为血清肌酐从基线翻倍或增加1 mg/dL或更多，或从基线计算出的肌酐清除率下降50%或更多）的发生率，在接受两性霉素B胆固醇硫酸盐复合物并同时使用环孢素或他克莫司的成人和儿童患者中为31%，而接受常规两性霉素B并同时使用这些药物的成人和儿童患者中为68%。在没有接受环孢素或他克莫司治疗的成人和儿童患者中，接受两性霉素B胆固醇硫酸盐复合物的肾脏毒性发生率为8%，而接受常规两性霉素B的发生率为35%。

In a randomized, double-blind study that evaluated use of conventional IV amphotericin B and amphotericin B cholesteryl sulfate complex in febrile neutropenic patients with normal baseline serum creatinine concentrations, the incidence of renal toxicity (defined as a doubling or an increase of 1 mg/dL or more from baseline serum creatinine or a 50% or greater decrease from baseline in calculated creatinine clearance) was 31% in adults and pediatric patients who received amphotericin B cholesteryl sulfate complex concomitantly with cyclosporine or tacrolimus compared with 68% in those who received conventional amphotericin B concomitantly with these agents. In adults and pediatric patients who did not receive cyclosporine or tacrolimus therapy, the incidence of renal toxicity was 8% in those who received amphotericin B cholesteryl sulfate complex and 35% in those who received conventional amphotericin B.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

两性霉素B的药代动力学因给药方式不同而有很大差异，无论是作为传统的两性霉素B（与去氧胆酸钠配伍）、两性霉素B胆固醇硫酸盐复合物、两性霉素B脂质复合物，还是两性霉素B脂质体，一种两性霉素B制剂的药代动力学参数不应用于预测任何其他两性霉素B制剂的药代动力学。

The pharmacokinetics of amphotericin B vary substantially depending on whether the drug is administered as conventional amphotericin B (formulated with sodium desoxycholate), amphotericin B cholesteryl sulfate complex, amphotericin B lipid complex, or amphotericin B liposomal, and pharmacokinetic parameters reported for one amphotericin B formulation should not be used to predict the pharmacokinetics of any other amphotericin B formulation.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

两性霉素B从胃肠道吸收不良，必须通过胃肠道外给药来治疗全身性真菌感染。在一项研究中，静脉输注30毫克两性霉素B（在几小时内给药）后立即，平均血药峰浓度约为1微克/毫升；当剂量为50毫克时，平均血药峰浓度大约为2微克/毫升。输注后立即，血清中最多只能解释10%的两性霉素B剂量。当每天给予30毫克的剂量或每隔一天给予60毫克的剂量时，记录的平均最低血药浓度约为0.4微克/毫升。

Amphotericin B is poorly absorbed from the GI tract and must be given parenterally to treat systemic fungal infections. In one study, immediately after completion of iv infusion of 30 mg of amphotericin B (administered over a period of several hours), average peak serum concentrations were about 1 ug/ml; when the dose was 50 mg, average peak serum concentrations were approximately 2 ug/ml. Immediately after infusion, no more than 10% of the amphotericin B dose can be accounted for in serum. Average minimum serum concentrations (recorded just prior to the next drug infusion) of approximately 0.4 ug/ml have been reported when doses of 30 mg were given daily or when doses of 60 mg were given every other day.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

两性霉素B的分布信息有限，尽管其分布显然是多室的。据报道，给予常规两性霉素B后，药物的分布体积为4 L/kg；而给予两性霉素B胆固醇硫酸盐后，稳态下的分布体积为3.8-4.1 L/kg。在给予常规两性霉素B静脉注射后，在炎症的胸膜、腹膜、滑膜和水状液中达到的两性霉素B浓度约为同时血浆浓度的60%；药物也分布到玻璃体、胸膜、心包、腹膜和滑液。据报道，两性霉素B能穿过胎盘，在羊水中达到低浓度。

Information on the distribution of amphotericin B is limited, although distribution is apparently multicompartmental. The volume of distribution of the drug following administration of conventional amphotericin B has been reported to be 4 L/kg; the volume of distribution at steady state after administration of amphotericin B cholesteryl sulfate is reported to be 3.8-4.1 L/kg. Amphotericin B concentrations attained in inflamed pleura, peritoneum, synovium, and aqueous humor following IV administration of conventional amphotericin B reportedly are about 60% of concurrent plasma concentrations; the drug also is distributed into vitreous humor, pleural, pericardial, peritoneal, and synovial fluid. Amphotericin B reportedly crosses the placenta and low concentrations are attained in amniotic fluid.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

经静脉注射常规两性霉素B后，脑脊液中的药物浓度大约为同时血清浓度的3%。为了达到抑菌作用的脑脊液浓度，通常需要通过鞘内给药。对于患有脑膜炎的患者，通过皮下储液器给予0.2-0.3毫克常规两性霉素B，可以使脑脊液中的药物浓度达到0.5-0.8微克/毫升的峰值；给药24小时后，脑脊液中的药物浓度为0.11-0.29微克/毫升。两性霉素B通过蛛网膜绒毛从脑脊液中移除，并似乎储存在大脑的细胞外间隙，这可能成为药物的储存库。

Following IV administration of conventional amphotericin B, CSF concentrations of the drug are approximately 3% of concurrent serum concentrations. To achieve fungistatic CSF concentrations, the drug must usually be administered intrathecally. In patients with meningitis, intrathecal administration of 0.2-0.3 mg of conventional amphotericin B via a subcutaneous reservoir has produced peak CSF concentrations of 0.5-0.8 ug/mL; 24 hours after the dose, CSF concentrations were 0.11-0.29 ug/mL. Amphotericin B is removed from the CSF by arachnoid villi and appears to be stored in the extracellular compartment of the brain, which may act as a reservoir for the drug.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  amphotericin B 在 吡啶 、 盐酸 、 sodium cyanoborohydride 、 氟化氢吡啶 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 生成
  参考文献：
  名称：

  通过霉菌胺的双烷基化显着提高了多烯大环内酯类的抗真菌活性。

  摘要：

  [反应：见正文]通过霉菌胺的双重还原烷基化反应合成了两性霉素B（AmB）的新衍生物。AmB的这些衍生物对酿酒酵母野生型菌株，特别是在抗AmB的白色念珠菌菌株的情况下，显示出优异的抗真菌活性。此外，由于与AmB相比血液毒性显着降低，因此这些化合物是潜在的候选药物。此外，可以将相同的霉菌胺修饰物应用于其他多烯大环内酯类化合物，如制霉菌素和匹马星，以提高其抗真菌活性。

  DOI：

  10.1021/ol060353o

文献信息

• Derivatives of Amphotericin B
  申请人：Revolution Medicines, Inc.

  公开号：US20160304548A1

  公开（公告）日：2016-10-20

  Disclosed are derivatives of amphotericin B (AmB) characterized by improved therapeutic index compared to AmB. The AmB derivatives include C16 ureas, carbamates, and amides according to Formula (I); C3′-substituted C16 ureas, carbamates, and amides according to Formula (II); C16 acyls according to Formula (III); C2′epi-C16 ureas, carbamates, and amides according to Formula (IV); and C16 oxazolidinone derivatives according to Formula (V). Also disclosed are pharmaceutical compositions comprising the AmB derivatives, and therapeutic methods of using the AmB derivatives.

  披露了与AmB相比具有改善的治疗指数的Amphotericin B（AmB）衍生物。这些AmB衍生物包括根据公式（I）的C16脲、碳酸酯和酰胺；根据公式（II）的C3′-取代的C16脲、碳酸酯和酰胺；根据公式（III）的C16酰基；根据公式（IV）的C2′epi-C16脲、碳酸酯和酰胺；以及根据公式（V）的C16噁唑烷酮衍生物。还披露了包括这些AmB衍生物的药物组合物，以及使用这些AmB衍生物的治疗方法。
• AMPHOTERICIN B DERIVATIVES
  申请人：Ramot at Tel-Aviv University Ltd.

  公开号：US20170043029A1

  公开（公告）日：2017-02-16

  Embodiments of the invention provide derivatives of Amphotericin B having increased solubility and reduced toxicity relative to AMB, while retaining antifungal activity against multiple clinical fungal isolates. Derivatives of AMB are provided comprising a polymer group having an amine group, the polymer linked to mycosamine via a relatively stable linker such as an amide linker. The derivatives may be of the general formula [I]: wherein R is H, C 1-4 alkyl or phenyl; R 2 is (CH 2 ) m wherein m is between 0 and 4; R 3 and R 4 are each independently H or C 1-4 alkyl, R 5 is H or OH, R 6 is selected from a group consisting of: amide and alkyl, and R 7 is a water-soluble polymer, and pharmaceutically acceptable salts, solvates, hydrates, diastereomers, and prodrugs of the compound of Formula [I].

  发明的实施例提供了阿莫西林B的衍生物，相对于AMB具有增加的溶解度和降低的毒性，同时保留对多种临床真菌分离物的抗真菌活性。提供了包括具有胺基的聚合物基团的AMB衍生物，该聚合物通过相对稳定的连接物（如酰胺连接物）与霉胺结合。这些衍生物可能符合以下一般公式[I]： 其中R为H、C1-4烷基或苯基；R2为(CH2)m，其中m介于0和4之间；R3和R4各自独立地为H或C1-4烷基，R5为H或OH，R6选自以下组合中的一种：酰胺和烷基，R7为水溶性聚合物，以及公认的药用盐、溶剂化合物、水合物、对映异构体和化合物[I]的前药。
• Amphotericin Derivatives
  申请人：Carreira Erick

  公开号：US20090186838A1

  公开（公告）日：2009-07-23

  The present invention provides new polyene macrolide derivatives which show very low toxicity while retaining high antifungal activity as compared with amphotericin B (AmB). These polyene macrolide derivatives comprise a polyene macrolide backbone having at least one free amino group, wherein the amino group is doubly alkylated with at least one hydrocarbon group carrying a total of at least two basic groups.

  本发明提供了新的多烯大环内酯衍生物，相比于两性霉素B（AmB），这些衍生物表现出非常低的毒性，同时保持高的抗真菌活性。这些多烯大环内酯衍生物包括至少具有一个自由氨基的多烯大环内酯骨架，其中该氨基被至少一个碳氢基团双烷基化，该碳氢基团携带至少两个碱性基团。
• SCALABLE SYNTHESIS OF REDUCED TOXICITY DERIVATIVE OF AMPHOTERICIN B
  申请人：THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ILLINOIS

  公开号：US20170233427A1

  公开（公告）日：2017-08-17

  Disclosed is a simplified, readily scalable series of individual methods that collectively constitute a method for the synthesis of C2′epiAmB, an efficacious and reduced-toxicity derivative of amphotericin B (AmB), beginning from AmB. Also provided are various compounds corresponding to intermediates in accordance with the series of methods.
• RESTORING PHYSIOLOGY WITH SMALL MOLECULE MIMICS OF MISSING PROTEINS
  申请人：The Board of Trustees of the University of Illinois

  公开号：US20180015115A1

  公开（公告）日：2018-01-18

  Disclosed are methods for treating a disease or condition characterized by decreased expression or reduced function of an ion channel, comprising administering to a subject in need thereof a therapeutically effective amount of a pore-forming polyene macrolide or pore-forming derivative thereof. For example, the pore-forming polyene macrolide may be amphotericin B (AmB), nystatin, or natamycin. The methods can be used to treat cystic fibrosis.