美罗培南 | 96036-03-2

• 物质功能分类: 原料药 - 抗生素类药物 - β-内酰胺酶抑制剂
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酰胺类
• 中文名称: 美罗培南
• 中文别名: 美诺配南；麦洛派南；3-[[5-[(二甲氨基)羰基]-3-吡咯烷基]硫代]-6-(1-羟乙基)-4-甲基-7-氧代-1-氮杂双环[3,2,0]庚-2-烯-2-羧酸；美洛培南；(-)-(4R,5S,6S)-3-[[(3S,5S)-5-(二甲基氨甲酰基)
• 英文名称: meropenem
• 英文别名: MEM；mer；MEC；merrem；MRP；(4R,5S,6S)-3-[(3S,5S)-5-(dimethylcarbamoyl)pyrrolidin-1-ium-3-yl]sulfanyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate
• CAS: 96036-03-2
• 化学式: C₁₇H₂₅N₃O₅S
• 分子量: 383.469
• InChiKey: DMJNNHOOLUXYBV-PQTSNVLCSA-N

物化性质

• 沸点：
  627.4±55.0 °C(Predicted)
• 密度：
  1.42±0.1 g/cm3(Predicted)
• 溶解度：
  不溶于乙醇； DMSO 中≥19.15 mg/mL；超声检测水中≥9.88 mg/mL
• 物理描述：
  Solid
• 蒸汽密度：
  6.85X10-18 mm Hg at 25 °C (est)
• 稳定性/保质期：

  Solutions of Meropenem (Meropenem concentrations ranging from 2.5 to 20 mg/mL) in Baxter Minibag Plus bags with Sodium Chloride Injection 0.9% may be stored for up to 4 hours at controlled room temperatures 15-25 °C (59-77 °F) or for up to 24 hours at 4 °C (39 °F). Solutions of Meropenem (Meropenem concentrations ranging from 2.5 to 20 mg/mL) in Baxter Minibag Plus bags with Dextrose Injection 5% may be stored up to 1 hour at controlled room temperatures 15-25 °C (59-77 °F) or for up to 6 hours at 4 °C (39 °F).

• 碰撞截面：
  192.42 Ų [M-H]-; 190.79 Ų [M+H]+

计算性质

• 辛醇/水分配系数(LogP)：
  -2.4
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  136
• 氢给体数：
  3
• 氢受体数：
  7

ADMET

代谢

主要不经改变地排出体外。有一个代谢物，它在微生物学上是无效的。

Primarily excreted unchanged. There is one metabolite which is microbiologically inactive.

来源:DrugBank

代谢

美罗培南有一个微生物学上不活跃的代谢物。

There is one metabolite of meropenem that is microbiologically inactive.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

静脉注射美罗培南长达14天的受药者中，有1%至6%报告了血清转氨酶升高。这些升高通常是短暂的、轻微且无症状的；很少需要调整剂量。美罗培南还与罕见的胆汁淤积性黄疸病例有关，这种黄疸通常在治疗1到3周后出现。可能出现免疫过敏特征，但很少显著。自身抗体罕见。大多数病例都是轻微且自限性的，但至少有一例与美罗培南治疗相关的胆管消失综合征已经发表（案例1）。尚未有报告称美罗培南导致急性肝衰竭。

Serum aminotransferase elevations have been reported in 1% to 6% of recipients of intravenous meropenem when given for up to 14 days. These elevations are usually transient, mild and asymptomatic; and rarely require dose adjustment. Meropenem has also been linked to rare cases of cholestatic jaundice that usually arises after 1 to 3 weeks of therapy. Immunoallergic features may be present, but are rarely prominent. Autoantibodies are rare. Most cases are mild and self-limited, but at least one instance of vanishing bile duct syndrome related to meropenem therapy has been published (Case 1). Meropenem has not been reported to cause acute liver failure.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：美罗培南

Compound:meropenem

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：低药物性肝损伤关注

DILI Annotation:Less-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

毒理性

• 药物性肝损伤

标签部分：警告和预防措施

Label Section:Warnings and precautions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 消除途径

大约70%的静脉给药剂量在12小时内以未改变的厄他培南形式在尿液中回收，此后很少能在尿液中检测到进一步的排泄。

Approximately 70% of the intravenously administered dose is recovered as unchanged meropenem in the urine over 12 hours, after which little further urinary excretion is detectable.

来源:DrugBank

吸收、分配和排泄

大约70%的静脉给药剂量在12小时内以未改变的厄他培南形式在尿液中回收，此后很少能检测到进一步的尿液排泄。在500毫克剂量给药后，厄他培南在尿液中的浓度超过10微克/毫升可维持长达5小时。

Approximately 70% of the intravenously administered dose is recovered as unchanged meropenem in the urine over 12 hours, after which little further urinary excretion is detectable. Urinary concentrations of meropenem in excess of 10 ug/mL are maintained for up to 5 hours after a 500 mg dose.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

美罗培南分布到大多数身体组织和体液中，包括支气管粘膜、肺、胆汁、妇科组织（子宫内膜、子宫肌层、卵巢、宫颈、输卵管）、肌肉、心脏瓣膜、皮肤、间质和腹膜液以及脑脊液。血浆蛋白结合率大约为2%。该药物部分代谢至少产生一个微生物学上无活性的代谢物。大约70%的静脉注射剂量以原药形式通过肾小管分泌和肾小球滤过作用随尿液排出。

Meropenem is distributed into most body tissues and fluids, including bronchial mucosa, lung, bile, gynecologic tissue (endometrium, myometrium, ovary, cervix, fallopian tube), muscle, heart valves, skin, interstitial and peritoneal fluid, and CSF. Plasma protein binding is approximately 2%. The drug is partially metabolized to at least one microbiologically inactive metabolite. About 70% of an IV dose is eliminated in urine as unchanged drug by tubular secretion and glomerular filtration.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在健康志愿者中，单次静脉输注美罗培南注射剂（静脉）30分钟后，500毫克剂量的平均峰血浆浓度约为23微克/毫升（范围14-26），1克剂量的平均峰血浆浓度约为49微克/毫升（范围39-58）。健康志愿者通过5分钟静脉推注美罗培南注射剂（静脉）后，500毫克剂量的平均峰血浆浓度约为45微克/毫升（范围18-65），1克剂量的平均峰血浆浓度约为112微克/毫升（范围83-140）。在静脉给药500毫克后，美罗培南的平均血浆浓度通常在给药后6小时降至约1微克/毫升。在使用500毫克每8小时一次或1克每6小时一次的给药方案的健康志愿者中，未观察到血浆中美罗培南的积累现象。

At the end of a 30 minute intravenous infusion of a single dose of Meropenem for injection (IV) in healthy volunteers, mean peak plasma concentrations of meropenem are approximately 23 ug/mL (range 14-26) for the 500 mg dose and 49 ug/mL (range 39-58) for the 1 g dose. A 5-minute intravenous bolus injection of Meropenem for injection (IV) in healthy volunteers results in mean peak plasma concentrations of approximately 45 ug/mL (range 18-65) for the 500 mg dose and 112 ug/mL (range 83-140) for the 1 g dose. Following intravenous doses of 500 mg, mean plasma concentrations of meropenem usually decline to approximately 1 ug/mL at 6 hours after administration. No accumulation of meropenem in plasma was observed with regimens using 500 mg administered every 8 hours or 1 g administered every 6 hours in healthy volunteers with normal renal function.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xi
• 安全说明：
  S26,S37/39
• 危险类别码：
  R36/37/38
• 海关编码：
  2933990090
• 储存条件：
  -20°C，密封保存，并保持干燥。

SDS

Material Safety Data Sheet

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Section 1. Identification of the substance
Product Name: Meropenem
Synonyms:

---

Section 2. Hazards identification
Harmful by inhalation, in contact with skin, and if swallowed.

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Section 3. Composition/information on ingredients.
Ingredient name: Meropenem
CAS number: 96036-03-2

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Section 4. First aid measures
Skin contact: Immediately wash skin with copious amounts of water for at least 15 minutes while removing
contaminated clothing and shoes. If irritation persists, seek medical attention.
Eye contact: Immediately wash skin with copious amounts of water for at least 15 minutes. Assure adequate
flushing of the eyes by separating the eyelids with fingers. If irritation persists, seek medical
attention.
Inhalation: Remove to fresh air. In severe cases or if symptoms persist, seek medical attention.
Ingestion: Wash out mouth with copious amounts of water for at least 15 minutes. Seek medical attention.

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Section 5. Fire fighting measures
In the event of a fire involving this material, alone or in combination with other materials, use dry
powder or carbon dioxide extinguishers. Protective clothing and self-contained breathing apparatus
should be worn.

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Section 6. Accidental release measures
Personal precautions: Wear suitable personal protective equipment which performs satisfactorily and meets local/state/national
standards.
Respiratory precaution: Wear approved mask/respirator
Hand precaution: Wear suitable gloves/gauntlets
Skin protection: Wear suitable protective clothing
Eye protection: Wear suitable eye protection
Methods for cleaning up: Mix with sand or similar inert absorbent material, sweep up and keep in a tightly closed container
for disposal. See section 12.
Environmental precautions: Do not allow material to enter drains or water courses.

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Section 7. Handling and storage
Handling: This product should be handled only by, or under the close supervision of, those properly qualified
in the handling and use of potentially hazardous chemicals, who should take into account the fire,
health and chemical hazard data given on this sheet.
Store in closed vessels, refrigerated.
Storage:

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Section 8. Exposure Controls / Personal protection
Engineering Controls: Use only in a chemical fume hood.
Personal protective equipment: Wear laboratory clothing, chemical-resistant gloves and safety goggles.
General hydiene measures: Wash thoroughly after handling. Wash contaminated clothing before reuse.

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Section 9. Physical and chemical properties
Appearance: Not specified
Boiling point: No data
No data
Melting point:
Flash point: No data
Density: No data
Molecular formula: C17H25N3O5S
Molecular weight: 383.5

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Section 10. Stability and reactivity
Conditions to avoid: Heat, flames and sparks.
Materials to avoid: Oxidizing agents.
Possible hazardous combustion products: Carbon monoxide, nitrogen oxides, sulfur oxides.

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Section 11. Toxicological information
No data.

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Section 12. Ecological information
No data.

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Section 13. Disposal consideration
Arrange disposal as special waste, by licensed disposal company, in consultation with local waste
disposal authority, in accordance with national and regional regulations.

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Section 14. Transportation information
Non-harzardous for air and ground transportation.

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Section 15. Regulatory information
No chemicals in this material are subject to the reporting requirements of SARA Title III, Section
302, or have known CAS numbers that exceed the threshold reporting levels established by SARA
Title III, Section 313.

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

半合成碳青霉烯类抗生素：美罗培南

美罗培南是继亚胺培南-西司他丁在美国上市后的另一个非肠道给药的半合成碳青霉烯类抗生素。它对各类需氧菌和厌氧菌，特别是产酶菌株、多重耐药菌株及以革兰阴性（G-）菌为主的严重感染、混合感染、院内感染和免疫缺陷者的感染具有良好的抗菌活性。

美罗培南与其他碳青霉烯类抗生素的对比

美罗培南、亚胺培南和帕尼培南这三种药物在抗菌作用上各有侧重：

1. 对厌氧菌的抗菌谱相似，但对需氧菌中的不发酵阴性菌，以美罗培南的活性最强。
2. 对中枢神经系统的不良反应：亚胺培南发生率最高，而美罗培南和帕尼培南较低。
3. 肾脱氢肽酶稳定性：美罗培南和帕尼培南对人肾脱氢肽酶稳定；亚胺培南需加用西司他丁。
4. 给药途径：亚胺培南和帕尼培南仅适用于静脉滴注，而美罗培南还可用肌内注射。

用药方法与用量 美罗培南注射液

• 规格: 0.5g; 0.25g。
• 溶液配制：以适宜的溶剂稀释后静脉滴注15-30分钟或直接用无菌注射用水稀释后在3-5分钟内静脉注射。

成人用药

• 静脉给药：常规剂量为每8小时给药500mg至1000mg；重度感染时的剂量可增加至每8小时500-2000mg。
• 特殊人群
  • 肾功能不全：肌酐清除率为26mL/min至50mL/min者，每12小时给药1000mg；肌酐清除率10mL/min至25mL/min者，每12小时给药500mg; 肌酐清除率小于10 mL/min者，每24小时给药500mg。
  • 轻度肝功能不全患者无需调整剂量；老年人因半衰期延长应减少剂量；透析患者在血液透析时建议增加剂量。

儿童用药

• 剂量为10-20mg/kg，每日3次。

不良反应

美罗培南的严重不良反应少见，但临床试验中可见以下症状：

1. 注射部位炎症、血栓性静脉炎、注射部位疼痛。
2. 皮疹、瘙痒、荨麻疹。
3. 腹痛、恶心、呕吐、腹泻。
4. 可逆性嗜酸细胞增多、血小板减少、中性粒细胞减少，部分患者出现直接或间接Coombs试验阳性。
5. 血清胆红素、转氨酶、碱性磷酸酶、乳酸脱氢酶浓度可逆性升高。
6. 头痛、感觉异常。
7. 口腔和阴道念珠菌感染。

药物相互作用

1. 与丙磺舒联合用药可能降低美罗培南的血浆清除率，延长其半衰期。
2. 与伤寒活疫苗同用可能导致免疫反应减弱。
3. 抗癫痫药可能与美罗培南合用时使其浓度降低。
4. 可能与其他药物（如齐多夫定、昂丹司琼、多种维生素、多西环素、地西泮、葡萄糖酸钙和阿昔洛韦等）产生配伍禁忌。

用途

抗感染类药，抗生素类药。

反应信息

• 作为反应物：
  描述：

  美罗培南 在 水 作用下， 以 四氢呋喃 为溶剂， 反应 5.0h， 生成 meropenem trihydrate
  参考文献：
  名称：

  [EN] A PROCESS FOR THE PREPARATION OF MEROPENEM
  [FR] PROCEDE DE PREPARATION DE MEROPENEM

  摘要：

  公开号：

  WO2006035300A3
• 作为产物：
  描述：

  (5R,6S,8R,2'S,4'S)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl)pyrrolidinylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]-hept-2-en-7-oxo-2carboxylate 在 palladium 10% on activated carbon 氢气 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 3.0h， 生成 美罗培南
  参考文献：
  名称：

  WO2007/31858

  摘要：

  公开号：
• 作为试剂：
  描述：

  保护美罗培南 、 乙酸乙酯 、 氢气 在 钯 钯 、 正丁醇 、 美罗培南 作用下， 以 水 为溶剂， 反应 2.5h， 以as obtained in Example 1的产率得到美罗培南
  参考文献：
  名称：

  PROCESS FOR PRODUCING CARBAPENEM COMPOUND

  摘要：

  本发明的目的是提供一种简便的方法，用于生产在抗微生物活性方面表现出色的（4R,5S,6S）-3-[[(3S,5S)-5-(二甲氨基甲酰基)-3-吡咯烷基]硫]-6-[(1R)-1-羟乙基]-4-甲基-7-氧代-1-氮杂双环[3.2.0]庚-2-烯-2-羧酸。本发明涉及一种连续生产（4R,5S,6S）-3-[[(3S,5S)-5-(二甲氨基甲酰基)-3-吡咯烷基]硫]-6-[(1R)-1-羟乙基]-4-甲基-7-氧代-1-氮杂双环[3.2.0]庚-2-烯-2-羧酸的方法，不需要分离/纯化反应中间体。

  公开号：

  US20100240886A1

文献信息

• [EN] ANTIBACTERIAL 8-PHENYLAMINO-3-(PYRAZOL-4-YL)IMIDAZO[1,2-A]PYRAZINE DERIVATIVES<br/>[FR] DÉRIVÉS ANTIBACTÉRIENS DE 8-PHÉNYLAMINO-3-(PYRAZOL-4-YL)IMIDAZO[1,2-A]PYRAZINE
  申请人：HOFFMANN LA ROCHE

  公开号：WO2021219578A1

  公开（公告）日：2021-11-04

  The invention provides novel imidazopyrazine derivatives having the general formula (I), wherein X and R3 to R9 are as described herein or pharmaceutically acceptable salts thereof, wherein X and R3 to R9 are as defined herein. Further provided are pharmaceutical compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds as medicaments, in particular methods of using the compounds as antibiotics for the treatment or prevention of bacterial infections and resulting diseases.

  这项发明提供了具有一般式(I)的新型咪唑吡嗪衍生物，其中X和R3至R9如本文所述或其药学上可接受的盐，其中X和R3至R9如本文所定义。还提供了包括这些化合物的药物组合物、制造这些化合物的方法以及将这些化合物用作药物的方法，特别是将这些化合物用作抗生素治疗或预防细菌感染及由此导致的疾病的方法。
• [EN] DERIVATIVES OF AMANITA TOXINS AND THEIR CONJUGATION TO A CELL BINDING MOLECULE<br/>[FR] DÉRIVÉS DE TOXINES D'AMANITES ET LEUR CONJUGAISON À UNE MOLÉCULE DE LIAISON CELLULAIRE
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2017046658A1

  公开（公告）日：2017-03-23

  Derivatives of Amernita toxins of Formula (I), wherein, formula (a) R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X, L, m, n and Q are defined herein. The preparation of the derivatives. The therapeutic use of the derivatives in the targeted treatment of cancers, autoimmune disorders, and infectious diseases.

  Amernita毒素的衍生物的化学式（I），其中，化学式（a）中的R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、X、L、m、n和Q在此处被定义。这些衍生物的制备。这些衍生物在靶向治疗癌症、自身免疫性疾病和传染病中的治疗用途。
• [EN] A CONJUGATE OF A CYTOTOXIC AGENT TO A CELL BINDING MOLECULE WITH BRANCHED LINKERS<br/>[FR] CONJUGUÉ D'UN AGENT CYTOTOXIQUE À UNE MOLÉCULE DE LIAISON CELLULAIRE AVEC DES LIEURS RAMIFIÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020257998A1

  公开（公告）日：2020-12-30

  Provided is a conjugation of cytotoxic drug to a cell-binding molecule with a side-chain linker. It provides side-chain linkage methods of making a conjugate of a cytotoxic molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and immunological disorders.

  提供了一种将细胞毒性药物与一个侧链连接分子结合的共轭物。它提供了制备细胞毒性分子与细胞结合配体的共轭物的侧链连接方法，以及在靶向治疗癌症、感染和免疫性疾病中使用该共轭物的方法。
• [EN] CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES<br/>[FR] DÉRIVÉ DE DIMÈRE DE PYRROLOBENZODIAZÉPINE RÉTICULÉ (PBD) ET SES CONJUGUÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020006722A1

  公开（公告）日：2020-01-09

  A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.

  一种新型的交联细胞毒剂，吡咯苯并二氮杂环二聚体（PBD）衍生物，以及它们与细胞结合分子的结合物，一种制备这些结合物的方法以及这些结合物的治疗用途。
• [EN] ANTIBACTERIAL COMPOUNDS<br/>[FR] COMPOSÉS ANTIBACTÉRIENS
  申请人：MASSACHUSETTS GEN HOSPITAL

  公开号：WO2019199979A1

  公开（公告）日：2019-10-17

  The present application provides compounds of formula: Methods of using these compounds for killing bacterial growth and treating bacterial infections are also provided.

  本申请提供了以下化合物的公式：还提供了使用这些化合物杀灭细菌生长和治疗细菌感染的方法。