非达霉素 | 873857-62-6

• 物质功能分类: 生物化工 - 抑制剂 - DNA损伤(DNA Damage)
• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酯类和类似物
• 中文名称: 非达霉素
• 英文名称: Fidaxomicin
• 英文别名: [(2R,3S,4S,5S,6R)-6-[[(3E,5E,8S,9E,11S,12R,13E,15E,18S)-12-[(2R,3S,4R,5S)-3,4-dihydroxy-6,6-dimethyl-5-(2-methylpropanoyloxy)oxan-2-yl]oxy-11-ethyl-8-hydroxy-18-[(1R)-1-hydroxyethyl]-9,13,15-trimethyl-2-oxo-1-oxacyclooctadeca-3,5,9,13,15-pentaen-3-yl]methoxy]-4-hydroxy-5-methoxy-2-methyloxan-3-yl] 3,5-dichloro-2-ethyl-4,6-dihydroxybenzoate
• CAS: 873857-62-6
• 化学式: C₅₂H₇₄Cl₂O₁₈
• 分子量: 1058.0
• InChiKey: ZVGNESXIJDCBKN-UUEYKCAUSA-N

物化性质

• 熔点：
  161 °C
• 沸点：
  1046.4±65.0 °C(Predicted)
• 密度：
  1.33
• 溶解度：
  可溶于氯仿（轻微加热）、DMSO（轻微加热）、甲醇（轻微加热）

计算性质

• 辛醇/水分配系数(LogP)：
  6.4
• 重原子数：
  72
• 可旋转键数：
  15
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  267
• 氢给体数：
  7
• 氢受体数：
  18

ADMET

代谢

口服给药后，芬达霉素通过异丁酰酯的水解转化为其主要和具有药理活性的代谢物OP-1118。由于细胞色素酶不参与芬达霉素的代谢，推测这种生物转化是由胃酸或肠道微粒体的酶活性介导的。

Following oral administration, fidaxomicin is transformed to its main and pharmacologically active metabolite, OP-1118, via hydrolysis at the isobutyryl ester. As cytochrome enzymes are not involved in the metabolism of fidaxomicin, it is speculated that this biotransformation is mediated by gastric acid or enzymatic activity of intestinal microsomes.

来源:DrugBank

毒理性

• 肝毒性

在大规模临床试验中，使用(fidaxomicin)(fidaxomicin)治疗10天与血清转氨酶升高率低(1%至3.2%)有关，但与比较药物(如万古霉素)相似(最高2.7%)。没有报告称(fidaxomicin)导致临床上明显的肝损伤。然而，其他口服大环内酯类抗生素与许多急性肝损伤病例有关，这些病例可能是严重的，并已导致死亡。大环内酯类相关肝损伤的发病通常在开始用药后1到3周，停药后也可能出现。损伤通常是胆汁淤积性的，但可能是混合性或肝细胞性的。肝细胞病例更可能是严重的，可能导致急性肝衰竭。然而，在大多数情况下，停用大环内酯类药物后4到8周内可恢复。然而，没有病例与(fidaxomicin)的使用有关，与其它大环内酯类药物不同，(fidaxomicin)不会通过口服吸收。

In large clinical trials, therapy with fidaxomicin for ten days was associated with a low rate of serum aminotransferase elevations [1% to 3.2%], but rates with comparator agents such as vancomycin were similar [up to 2.7%]. There have been no reports of clinically apparent liver injury attributed to fidaxomicin. However, other oral macrolide antibiotics have been linked to many episodes of acute liver injury which can be severe and have resulted in fatalities. The onset of macrolide associated liver injury is typically 1 to 3 weeks after starting the drug and can arise after it is stopped. The injury is typically cholestatic, but can be mixed or hepatocellular. The hepatocellular cases are more likely to be severe and can result in acute liver failure. However, in most instances, recovery occurs within 4 to 8 weeks of withdrawal of the macrolide. No such cases, however, have been linked to use of fidaxomicin, which unlike the other macrolides is not absorbed orally.

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

母乳喂养期间使用总结：目前没有关于母乳喂养期间使用(fidaxomicin)(fidaxomicin)的信息。由于口服吸收不良，它不太可能进入婴儿的血液或对哺乳婴儿产生任何不良影响。 对哺乳婴儿的影响：截至修订日期，没有找到相关的已发布信息。 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。

◉ Summary of Use during Lactation:No information is available on the use of fidaxomicin during breastfeeding. Because it is poorly absorbed orally, it is not likely to reach the bloodstream of the infant or cause any adverse effects in breastfed infants. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 蛋白质结合

由于口服给药后菲达克西林的全身吸收最小，因此关于菲达克西林的血浆蛋白结合率的信息有限。

Since fidaxomicin has minimal systemic absorption following oral administration, there is limited information on the plasma protein binding profile of fidoxamicin.

来源:DrugBank

吸收、分配和排泄

• 吸收

在健康成年人中，单次口服200毫克(fidaxomicin)后，(fidaxomicin)及其主要代谢物OP-1118的Cmax分别为5.20 ± 2.81 ng/mL和12.0 ± 6.06，(fidaxomicin)的Tmax中位数为2小时。口服(fidaxomicin)后(fidaxomicin)的全身吸收最小。在一项涉及高脂饮食与空腹条件下的健康成年人的食物效应研究中，(fidaxomicin)和OP-1118的Cmax分别降低了21.5%和33.4%;但是，这种影响被认为是临床上不重要的，因为(fidaxomicin)的疗效不依赖于全身循环中的药物浓度。

Following oral administration of a single dose of 200 mg fidaxomicin in healthy adults, the Cmax of fidaxomicin and its main metabolite OP-1118 were 5.20 ± 2.81 ng/mL and 12.0 ± 6.06, respectively. The median Tmax of fidaxomicin was 2 hours. The systemic absorption of fidaxomicin following oral administration is minimal. In a food-effect study involving healthy adults in either with a high-fat meal versus under fasting conditions, the Cmax of fidaxomicin and OP-1118 were decreased by 21.5% and 33.4%, respectively; however, this effect is deemed to be clinically insignificant as the therapeutic action of fidaxomicin does not depend on drug concentrations in the systemic circulation.

来源:DrugBank

吸收、分配和排泄

• 消除途径

口服给药后，芬达霉素主要通过粪便排泄。在一项研究中，健康成年人单次服用200毫克和300毫克芬达霉素后，超过92%的剂量以未改变的母药或代谢物的形式在粪便中被回收。在另一项针对健康成年人的研究中，大约0.59%的口服剂量（200毫克）以主要代谢物OP-1118的形式在尿液中回收。

Following oral administration, fidaxomicin is mainly excreted in feces. More than 92% of the dose was recovered in the faces as either the unchanged parent drug or metabolites in one study consisting of healthy adults receiving single doses of 200 mg and 300 mg of fidaxomicin. In another study of healthy adults, approximately 0.59% fo the oral dose (200 mg) administered was recovered in the urine as the main metabolite, OP-1118.

来源:DrugBank

吸收、分配和排泄

• 分布容积

Fidaxomicin 口服给药时主要局限于胃肠道。关于 Fidaxomicin 的分布容积信息有限。

Fidaxomicin is mainly confined to the gastrointestinal tract when orally administered. There is limited information on the volume of distribution of fidaxomicin.

来源:DrugBank

吸收、分配和排泄

• 清除

关于菲达克西汀的清除信息有限。

There is limited information on the clearance of fidaxomicin.

来源:DrugBank

安全信息

• 危险性防范说明：
  P201,P202,P264,P270,P281,P301+P312,P308+P313,P330,P405,P501
• 危险性描述：
  H302,H361

制备方法与用途

大环内酯类抗生素——非达霉素（fidaxomicin，Dificid）

非达霉素由Optimer公司研发，并于2011年5月27日获得FDA批准。这种药物是一种新颖机制的大环内酯类抗生素，主要通过抑制细菌的RNA聚合酶来迅速对抗难治梭状芽孢杆菌感染（CDI），疗效优于现有药物。其安全性和有效性已在两项大规模多中心、随机、双盲、活性药物对照临床试验中得到验证。

非达霉素具有以下化学性质：它是德干高原游动放线菌或桔橙指孢囊菌的发酵产物，属于新18元大环内酯化合物，分子量为1058.04，分子式为C32H74Cl2O18，在体内可生成活性代谢物OP-1118。

非达霉素通过与RNA多聚酶结合抑制细菌增殖。大多数RNA聚合酶由五个亚单位组成：（α2ββ’ω），核心催化酶加上一个负责启动子识别的б亚单位。在艰难梭状芽孢杆菌中，这种б亚单位不同于其他细菌株，目前体外研究未发现其与其它抗菌药物交叉耐药。

非达霉素及其主要代谢物OP-1118是P-糖蛋白外流转运载体的底物。非达霉素已与作用于P-糖蛋白底物及其抑制剂之间相互作用的研究，以及与CYP450同功酶3A4、2C9及2C19之间的相互作用进行了评估。研究药物包括环孢菌素、地高辛、咪达唑仑、奥美拉唑及华法林等。尽管环孢菌素可使非达霉素的最高血药浓度增加近一倍，但由于其浓度仍在ng/mL范围内，因此这些变化没有临床意义。对于其他药物，没有观察到非达霉素药动学方面的改变。

Fidaxomicin (OPT-80, PAR-101) 是一种窄谱的大环类抗生素，抑制RNA聚合酶σ亚基。

体外研究表明，非达霉素在开放的RNAP-DNA复合体形成之前通过结合DNA模板-RNA聚合酶（RNAP）复合体而抑制RNA聚合酶。这会抑制蛋白质合成，并引发易感生物体如艰难梭状芽孢杆菌的细胞凋亡。

体内研究显示，对于90%的生物体，非达霉素抗艰难梭状芽孢杆菌的最小抑菌浓度为0.9978到2 μg/mL。单次给药或多次给药后，低于定量下限的血药浓度表明其是非全身吸收的，而粪便中的浓度则很高且呈浓度依赖性。Cmax = 2小时；Tmax = 5.2 ng/mL；AUC = 14 ng•hr/mL。非达霉素能够被胃酸或肠道微粒水解成更小的活性代谢物（OP-1118），细胞色素酶系统不参与其代谢过程。

文献信息

• 18-Membered macrocycles and analogs thereof
  申请人：Shue Youe-Kong

  公开号：US20080269145A1

  公开（公告）日：2008-10-30

  The present invention relates generally to the 18-membered macrocyclic antimicrobial agents called Tiacumicins, specifically, OPT-80 (which is composed almost entirely of the R-Tiacumicin B), pharmaceutical compositions comprising OPT-80, and methods using OPT-80. In particular, this compound is a potent drug for the treatment of bacterial infections, specifically C. difficile infections.

  本发明涉及18元大环抗微生物剂Tiacumicins，具体地说是OPT-80（几乎完全由R-Tiacumicin B组成），包括OPT-80的制药组合物以及使用OPT-80的方法。特别地，该化合物是治疗细菌感染，特别是C. difficile感染的有效药物。
• FIDAXOMICIN PURIFICATION METHOD
  申请人：Zhejiang Hisun Pharmaceutical Co. Ltd.

  公开号：EP3168225A1

  公开（公告）日：2017-05-17

  A fidaxomicin purification method, comprising: fermenting Actinoplanes sp. HS-16-20 to generate fermented liquid; conducting solid/liquid separation on the fermented liquid, soaking mycelium in an organic solvent, and filtering to obtain a solution containing fidaxomicin; treating the solution with nanofiltration concentrate, and separating to obtain fidaxomicin crude product; conducting preparative column chromatography on the fidaxomicin crude product, eluting with an acid aqueous solution containing an organic solvent, and separating to obtain the refined fidaxomicin product.

  一种非达霉素纯化方法，包括：发酵放线菌 HS-16-20 产生发酵液；对发酵液进行固/液分离，将菌丝体浸泡在有机溶剂中并过滤，得到含有非达霉素的溶液；处理放线菌 HS-16-20 产生发酵液；对发酵液进行固液分离，将菌丝浸泡在有机溶剂中，过滤得到含有非达霉素的溶液；用纳滤浓缩液处理溶液，分离得到非达霉素粗品；对非达霉素粗品进行制备柱层析，用含有有机溶剂的酸性水溶液洗脱，分离得到精制的非达霉素产品。
• MACROCYCLIC POLYMORPHS, COMPOSITIONS COMPRISING SUCH POLYMORPHS, METHODS OF MANUFACTURE AND USE THEREOF
  申请人：Merck Sharp & Dohme Corp.

  公开号：EP2125850B1

  公开（公告）日：2018-05-30
• MACROLIDE POLYMORPHS, COMPOSITIONS COMPRISING SUCH POLYMORPHS, AND METHODS OF USE AND MANUFACTURE THEREOF
  申请人：Chiu Yu-Hung

  公开号：US20070259949A1

  公开（公告）日：2007-11-08

  The invention relates to novel forms of compounds displaying broad spectrum antibiotic activity, especially crystalline polymorphic forms and amorphous forms of such compounds, compositions comprising such crystalline polymorphic forms and amorphous forms of such compounds, processes for manufacture and use thereof. The compounds and compositions of the invention are useful in the pharmaceutical industry, for example, in the treatment or prevention of diseases or disorders associated with the use of antibiotics, chemotherapies, or antiviral therapies, including, but not limited to, colitis, for example, pseudo-membranous colitis; antibiotic associated diarrhea; and infections due to Clostridium difficile (“ C. difficile ”), Clostridium perfringens (“ C. perfringens ”), Staphylococcus species, for example, methicillin-resistant Staphylococcus , or Enterococcus including Vancomycin-resistant enterococci.
• Macrocyclic Polymorphs, Compositions Comprising Such Polymorphs and Methods of Use and Manufacture Thereof
  申请人：CHIU Yu-Hung

  公开号：US20100010076A1

  公开（公告）日：2010-01-14

  The invention relates to novel forms of compounds displaying broad spectrum antibiotic activity, especially crystalline polymorphic forms and amorphous forms of such compounds, compositions comprising such crystalline polymorphic forms and amorphous forms of such compounds, processes for manufacture and use thereof. The compounds and compositions of the invention are useful in the pharmaceutical industry, for example, in the treatment or prevention of diseases or disorders associated with the use of antibiotics, chemotherapies, or antiviral therapies, including, but not limited to, colitis, for example, pseudo-membranous colitis; antibiotic associated diarrhea; and infections due to Clostridium difficile (“ C. difficile ”), Clostridium perfringens (“ C. perfringens ”), Staphylococcus species, for example, methicillin-resistant Staphylococcus, or Enterococcus including Vancomycin-resistant enterococci.