(1R,35R)-33-(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 | 1397-89-3

• 物质功能分类: 原料药 - 抗生素类药物 - 多烯类药
• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (1R,35R)-33-(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
• CAS: 1397-89-3
• 化学式: C₄₇H₇₃NO₁₇
• 分子量: 924.1
• InChiKey: APKFDSVGJQXUKY-JOFRGCNDSA-N

物化性质

• 熔点：
  >170°C
• 比旋光度：
  D24 +333° (acidic DMF); -33.6° (0.1N methanolic HCl)
• 沸点：
  804.34°C (rough estimate)
• 密度：
  1.34
• 溶解度：
  无菌水：20 mg/mL作为储存液。储存液应储存在−20°C。在37℃下稳定保存3天。
• 物理描述：
  Amphotericin b is a bright yellow powder. (NTP, 1992)
• 颜色/状态：
  Deep yellow prisms or needles from n,n-dimethylformamide
• 气味：
  ODORLESS OR PRACTICALLY SO
• 稳定性/保质期：
  Solids and solutions appear stable for long periods between pH 4 and 10 when stored at moderate temperature out of light and air.
• 旋光度：
  Specific optical rotation at 24 °C/D: +333 deg (acidic N,N-dimethylformamide); -33.6 deg (0.1 N methanolic hydrochloric acid)
• 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)：
  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

轻度和短暂的肝酶升高发生在多达20%的使用两性霉素的患者中。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。肝脏损伤在开始治疗后的4到14天就会出现，通常表现为肝细胞或混合模式的酶升高。大多数患者没有症状或黄疸。停止治疗后，恢复迅速。此外，尽管罕见，但有一些明显的例子报告指出，在开始使用两性霉素后的几天内出现了高胆红素血症，升高的主要是直接（结合）胆红素部分。这些患者出现了肉眼可见的黄疸，但没有全身症状，血清ALT或碱性磷酸酶水平升高最小，没有明显的肝脏损伤证据。最后，有报道称在使用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，除非有必要用来控制对两性霉素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）可能会增加接受两性霉素B治疗的患者出现肾毒性、支气管痉挛和低血压的风险，因此此类联合治疗应非常谨慎使用。

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降低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的药代动力学因药物是以传统两性霉素B（与去氧胆酸钠配方）、两性霉素B胆固醇硫酸盐复合物、两性霉素B脂质体复合物还是两性霉素B脂质体形式给药而有很大差异，一种两性霉素B制剂的药代动力学参数不应用来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，必须通过胃肠道外途径给药以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（在几小时内输注完毕）后，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。输注后即刻，血清中至多能解释10%的两性霉素B剂量。当每日给予30毫克剂量或每隔一天给予60毫克剂量时，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

静脉注射传统两性霉素B后，脑脊液（CSF）中的药物浓度大约是同期血清浓度的3%。为了达到抑菌作用的CSF浓度，通常需要通过鞘内给药。对于患有脑膜炎的患者，通过皮下储液器鞘内给药0.2-0.3毫克的传统两性霉素B，可以产生0.5-0.8微克/毫升的脑脊液峰值浓度；给药24小时后，脑脊液浓度维持在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)

安全信息

• 危险等级：
  6.1(b)
• 危险品标志：
  Xi,Xn,T,C
• 安全说明：
  S26,S36,S36/37/39,S45
• 危险类别码：
  R22,R40,R36/37/38,R23/24/25
• WGK Germany：
  3
• 海关编码：
  29419090
• 危险品运输编号：
  UN 1759 8/PG 3
• RTECS号：
  BU2625000
• 包装等级：
  III
• 危险类别：
  6.1(b)

制备方法与用途

两性霉素B是一种用于治疗严重真菌感染的重要药物。它通过与真菌细胞膜上的固醇结合，破坏细胞膜的通透性，导致重要物质流失，从而杀死或抑制真菌生长。

主要特点

• 抗菌谱广：对多种真菌包括新型隐球菌、白色念珠菌等都有强大作用。
• 毒性较高：治疗剂量下可能会引起一些副作用如肾功能损害、发热和寒战、低钾血症等。
• 不同剂型：
  • 普通两性霉素B
  • 脂质体两性霉素B，减少了对肾脏的毒性。

化学性质

• 外观与溶解性：淡黄色至橙黄色针状结晶或粉末。不溶于水和乙醇。
• 稳定性：容易被光、热和酸破坏。
• 气味与味道：几乎无味。

生产方法

使用节链霉菌进行发酵提取，经过一系列纯化步骤得到最终产品。

使用注意事项

1. 严格按照医嘱用药，避免过量。
2. 注意观察可能出现的副作用，并及时报告医生。
3. 长期或高剂量使用可能需要定期监测肾功能和电解质平衡。

替代品与新制剂

为了减少传统两性霉素B的一些毒性反应，开发了脂质体形式的两性霉素B。这种制剂能够更有效地靶向真菌细胞，并减少对正常人体组织的影响。

总之，两性霉素B是一种非常有效的抗真菌药物，但由于其较强的毒性和某些限制，在使用时需要高度谨慎并严格遵循医疗指导。