Lefamulin | 1061337-51-6

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: Lefamulin
• 英文别名: [(1S,2R,3S,4S,6R,7R,8R)-4-ethenyl-3-hydroxy-2,4,7,14-tetramethyl-9-oxo-6-tricyclo[5.4.3.01,8]tetradecanyl] 2-[(1R,2R,4R)-4-amino-2-hydroxycyclohexyl]sulfanylacetate
• CAS: 1061337-51-6
• 化学式: C₂₈H₄₅NO₅S
• 分子量: 507.7
• InChiKey: KPVIXBKIJXZQJX-CSOZIWFHSA-N

物化性质

• 沸点：
  618.6±55.0 °C(Predicted)
• 密度：
  1.19±0.1 g/cm3(Predicted)
• 溶解度：
  DMF：16mg/mL；二甲基亚砜：12mg/mL；乙醇：3mg/mL； PBS（pH 7.2）：0.25 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  35
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  135
• 氢给体数：
  3
• 氢受体数：
  7

ADMET

代谢

CYP3A4是负责lefamulin代谢的主要酶。

CYP3A4 is the main enzyme responsible for the metabolism of lefamulin.[A183167,L8093]

来源:DrugBank

毒理性

• 肝毒性

血清ALT、AST和GGT水平升高至正常上限的3倍以上的情况在服用lefamulin的患者中（n=641）发生了1.2%至3.5%，但血清酶水平升高的率和严重程度与比较组（莫西沙星：n=641）相似。这些酶水平升高通常是轻至中度的严重程度，持续时间有限，并且不伴随症状或黄疸。目前尚未有报告指出lefamulin导致的临床上明显的肝损伤，但这个抗生素的普遍使用有限。

Serum ALT, AST and GGT elevations above 3 times the upper limit of normal occurred in 1.2% to 3.5% of patients treated with lefamulin (n=641), but rates and severity of serum enzyme elevations were similar to those in comparator arms (moxifloxacin: n=641). These enzymes elevations were usually mild-to-moderate in severity, self-limited in duration and not accompanied by symptoms or jaundice. Instances of clinically apparent liver injury attributable to lefamulin have not been reported but this antibiotic has had limited general use.

来源:LiverTox

毒理性

• 毒性总结

在lefamulin过量使用的情况下，应密切监测患者并根据症状和体征提供支持性治疗。这种药物及其活性代谢物无法通过透析去除。[L8093]

In the case of overdose with lefamulin, the patient should be monitored closely and provided with supportive treatment, according to symptoms and signs. This drug and its active metabolite are not removable by dialysis.[L8093]

来源:DrugBank

毒理性

• 蛋白质结合

乐卡霉素的平均血浆蛋白结合率在健康成年人中为94.8%至97.1%。[L8093] 一项系统评价确定血浆蛋白结合率为80-87%。[A183167]

The average plasma protein binding of lefamulin is between 94.8 to 97.1% in healthy adults.[L8093] A systematic review identifies the plasma protein binding at 80-87%.[A183167]

来源:DrugBank

吸收、分配和排泄

• 吸收

在一项针对健康受试者的药代动力学研究中，口服给药后，来法米林被迅速吸收。静脉制剂的中位Tmax测量值为1.00小时，片剂制剂为1.76小时。在稳态剂量下，口服来法米林的Cmax为37.1微克/毫升。该药物在稳态浓度下的AUC为49.2微克·小时/毫升。口服片的估计生物利用度为25%。临床研究发现，在饱食状态下，来法米林的AUC降低了大约10-28%。为了优化吸收，应在餐前至少1小时或餐后至少2小时用水服用此药。

In a pharmacokinetic study of healthy subjects, lefamulin was rapidly absorbed after oral administration. The median Tmax was measured at 1.00 h for the intravenous preparation and 1.76 h for the tablet preparation.[A183227]At steady-state doses, the Cmax of oral lefamulin is 37.1 mcg/mL.[L8093] The AUC at steady-state concentrations of this drug is 49.2 mcg·h/mL. The estimated bioavailability of the oral tablets is 25%. Clinical studies have found that the AUC of lefamulin is decreased by about 10-28% in the fed state.[A183167] To optimize absorption, this drug should be administered a minimum of 1 hour before a meal or, at minimum, 2 hours after a meal with water.[L8093]

来源:DrugBank

吸收、分配和排泄

• 消除途径

Lefamulin主要通过消化道排出，大约14%通过肾脏排出。[A183269] 在健康成年志愿者的临床试验中，给予了放射性标记的Lefamulin剂量。当通过静脉给药时，发现总放射性在粪便中的平均排出量为77.3%，其中4.2%至9.1%为未改变的药物。通过口服给药后，在粪便中测得的总放射性为88.5%，其中7.8-24.8%为未改变的药物。在尿液中，静脉给药后未改变的药物排出量为15.5%，其中9.6-14.1%为未改变的药物，口服给药后为5.3%。[L8093]

Lefamulin is largely excreted by the gastrointestinal tract and about 14% excreted by the kidneys.[A183269] In healthy adult volunteers during clinical trials, a radiolabeled dose of lefamulin was administered. The total radioactivity found to be excreted in the feces was 77.3% on average with 4.2% to 9.1% as unchanged drug when the drug was administered via the intravenous route. A total radioactivity of 88.5% was measured in the feces with 7.8-24.8% as unchanged drug after a dose administered via the oral route. In the urine, it was found to be 15.5% with 9.6-14.1% excretd as unchanged drug after an intravenous dose and 5.3% after an oral dose.[L8093]

来源:DrugBank

吸收、分配和排泄

• 分布容积

社区获得性细菌性肺炎患者的左氟米星平均分布容积为86.1升，但范围可以从34.2升到153升。[L8093] 在临床研究中，已经显示左氟米星在肺组织中显著浓缩，这可能增加了其在治疗肺炎中的有效性。[A183167] 给药后，观察到左氟米星渗透到各种组织中，在肺上皮细胞液中的浓度大约是在血浆中浓度的6倍。[A183239] 动物研究表明，左氟米星能穿过胎盘。[L8093]

The average volume of distribution of lefamulin is 86.1 L in patients with community-acquired bacterial pneumonia, but can range from 34.2 to 153 L.[L8093] During clinical studies, lefamulin has been shown to significantly concentrate in the lung tissue, likely increasing its effectiveness in treating pneumonia.[A183167] After lefamulin is administered, penetration into various tissues is observed, and is about 6 times greater in concentration in the fluid of the pulmonary epithelium, when compared with concentrations in the plasma.[A183239] Animal studies demonstrate that lefamulin crosses the placenta.[L8093]

来源:DrugBank

吸收、分配和排泄

• 清除

lefamulin的总清除率在注射剂量后已确定范围为2.94至30.0升/小时。

The total body clearance of lefamulin has been determined to range from 2.94 to 30.0 L/h after an injected dose.[L8093]

来源:DrugBank

制备方法与用途

来法莫林是一种抗生素，也是一种50S核糖体亚基调节剂。2019年8月19日，它获得了美国食品药品管理局（FDA）的批准，用于治疗细菌感染。

文献信息

• PLEUROMUTILIN DERIVATIVES FOR THE TREATMENT OF DISEASES MEDIATED BY MICROBES
  申请人：Mang Rosemarie

  公开号：US20120029072A1

  公开（公告）日：2012-02-02

  Disclosed are pleuromutilin derivatives of formula (I) an their use in the treatment of diseases mediated by microbes.

  本发明涉及公开的式（I）的多粘菌素衍生物及其在治疗由微生物介导的疾病中的应用。
• PROCESS FOR THE PREPARATION OF PLEUROMUTILINS
  申请人：Riedl Rosemarie

  公开号：US20130079400A1

  公开（公告）日：2013-03-28

  Process for the preparation of a compound of formula I in the form of a single stereoisomer in crystalline form, comprising deprotecting the amine group in a compound of formula IIa or in a mixture of a compound of formula IIa with a compound of formula IIb and isolating a compound of formula I from the reaction mixture; compounds and salts of compounds of formula I in crystalline form; pharmaceutical compositions comprising such salts; processes for the preparation of intermediates and intermediates in a process for the preparation of a compound of formula I.

  制备公式I化合物的过程，以晶体形式存在于单一立体异构体中，包括将公式IIa化合物中的胺基去保护基，或在公式IIa化合物与公式IIb化合物的混合物中去保护基，并从反应混合物中分离出公式I化合物；以晶体形式存在的公式I化合物及其盐；包含这些盐的药物组合物；制备中间体的过程以及制备公式I化合物的过程中的中间体。
• Crystal structure of the large ribosomal subunit from S. aureus
  申请人：Yeda Research and Development Co. Ltd.

  公开号：US10556934B2

  公开（公告）日：2020-02-11

  A composition-of-matter comprising a crystallized form of a large ribosomal (50S) subunit of a pathogenic bacterium, and the atomic coordinates of the three-dimensional structure thereof are provided herein, as well as methods for crystallizing the same, and using the atomic coordinates of the same to design de novo ligands with high specificity thereto.

  本文提供了一种包含病原菌大核糖体（50S）亚基结晶形式的物质组合物及其三维结构的原子坐标，以及结晶该物质组合物和利用该物质组合物的原子坐标设计对其具有高特异性的新配体的方法。
• CRYSTALLINE FORM OF A PLEUROMUTILIN
  申请人：Nabriva Therapeutics AG

  公开号：EP2576505B1

  公开（公告）日：2017-11-29
• US8153689B2
  申请人：——

  公开号：US8153689B2

  公开（公告）日：2012-04-10