厄他培南 | 153832-46-3

• 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: 厄他培南
• 中文别名: (4R,5R,6S)-3-[(3S,5S)-5-[(3-羧基苯基)氨基甲酰基]吡咯烷-3-基]硫-6-(1-羟乙基)-4-甲基-7-氧代-1-氮杂双环[3.2.0]庚-2-烯-2-甲酸；美洛培南母核；(4R,5R,6S)-3-[(3S,5S)-5-[(3-羧基苯基)氨基甲酰基]吡咯烷-3-基]硫-6-(1-羟乙基)-4-甲基-7-氧代-1
• 英文名称: ertapenem
• 英文别名: (4R,5S,6S)-3-[(3S,5S)-5-[(3-carboxyphenyl)carbamoyl]pyrrolidin-3-yl]sulfanyl-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid；ertapenam；etrapenem；INVANZ；ERT；(4R,5S,6S)-3-[(3S,5S)-5-[(3-carboxyphenyl)carbamoyl]pyrrolidin-3-yl]sulfanyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
• CAS: 153832-46-3
• 化学式: C₂₂H₂₅N₃O₇S
• 分子量: 475.522
• InChiKey: JUZNIMUFDBIJCM-ANEDZVCMSA-N

物化性质

• 沸点：
  813.9±65.0 °C(Predicted)
• 密度：
  1.55±0.1 g/cm3(Predicted)
• 溶解度：
  溶于DMSO、甲醇
• 物理描述：
  Solid
• 蒸汽压力：
  3.56X10-24 mm Hg at 25 °C (est)
• 亨利常数：
  Henry's Law constant = 7.68X10-29 atm-cu m/mol at 25 °C (est)
• 稳定性/保质期：

  The reconstituted solution, immediately diluted in 0.9% Sodium Chloride Injection, may be stored at room temperature (25 °C) and used within 6 hours or stored for 24 hours under refrigeration (5 °C) and used within 4 hours after removal from refrigeration. Solutions of ertapenem should not be frozen.

计算性质

• 辛醇/水分配系数(LogP)：
  -1.5
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  182
• 氢给体数：
  5
• 氢受体数：
  9

ADMET

代谢

头孢他啶是一种碳青霉烯类抗生素，在大鼠、猴和人身上的代谢和分布进行了研究。斯普拉格-道莱大鼠和恒河猴通过静脉给药给予放射性标记的头孢他啶（分别为60和30 mg kg(-1)），健康的正常志愿者接受单一固定剂量1000 mg。收集尿液和粪便以确定总放射性。在健康志愿者中，(14)C-头孢他啶通过水解代谢到β-内酰胺环开环衍生物和未改变药物的肾排泄而消除。大约相等的量被排泄为β-内酰胺环开环代谢物和未改变的药物（分别为剂量的36.7%和37.5%）。在人体中，次要酰胺水解产物约占剂量的1%。大约10%的给药放射性在粪便中回收，这表明有一小部分通过胆汁和/或肠道排泄。在动物中，更大比例的剂量通过代谢消除；未改变药物的排泄在大鼠和猴中分别占剂量的17%和5%。在猴中，β-内酰胺环开环和酰胺水解代谢物分别占剂量的74.8%和7.59%，而在大鼠中，这些代谢物分别占剂量的31.9%和20%。用新鲜大鼠组织匀浆的体外研究表明，肺和肾是介导β-内酰胺环开环代谢物形成的主要器官。脱氢肽酶-I的特异性抑制剂西拉司丁在大鼠中抑制了头孢他啶的体内和体外代谢，这强烈表明肺和肾中头孢他啶的水解是由这种酶介导的。

The disposition and metabolism of ertapenem, a carbapenem antibiotic, was examined in rat, monkey and man. Sprague-Dawley rats and Rhesus monkeys were given, by intravenous administration, radiolabelled doses of ertapenem (60 and 30 mg kg(-1), respectively), and healthy normal volunteers received a single fixed dose of 1000 mg. Urine and feces were collected for determination of total radioactivity. In healthy volunteers, (14)C-ertapenem was eliminated by a combination of hydrolytic metabolism to a beta-lactam ring-opened derivative and renal excretion of unchanged drug. Approximately equal amounts were excreted as a beta-lactam ring-opened metabolite and unchanged drug (36.7 and 37.5% of dose, respectively). A secondary amide hydrolysis product accounted for about 1% of the dose in man. About 10% of the administered radioactivity was recovered in feces, which suggested that a minor fraction underwent biliary and/or intestinal excretion. In animals, a greater fraction of the dose was eliminated via metabolism; excretion of unchanged drug accounted for 17 and 5% of dose in rats and monkeys, respectively. In monkeys, the beta-lactam ring-opened and amide hydrolysis metabolites accounted for 74.8 and 7.59% of the dose, respectively, whereas in rats, these metabolites accounted for 31.9 and 20% of dose, respectively. In vitro studies with fresh rat tissue homogenates indicated that lung and kidney were the primary organs involved in mediating formation of the beta-lactam ring-opened metabolite. The specific inhibitor of dehydropeptidase-I, cilastatin, inhibited the in vivo and in vitro metabolism of ertapenem in rats, which suggested strongly that the hydrolysis of ertapenem in lung and kidney was mediated by this enzyme.

来源:Hazardous Substances Data Bank (HSDB)

代谢

厄他培南对多种β-内酰胺酶（包括青霉素酶、头孢菌素酶和广谱β-内酰胺酶）的水解稳定。厄他培南可被金属β-内酰胺酶水解。

Ertapenem is stable against hydrolysis by a variety of beta-lactamases, including penicillinases, and cephalosporinases and extended spectrum beta-lactamases. Ertapenem is hydrolyzed by metallo-beta-lactamases.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在健康的年轻成年人中，静脉注射1克放射性标记的厄他培南后，血浆中的放射性物质主要（94%）为厄他培南。厄他培南的主要代谢物是通过β-内酰胺环水解形成的无活性的开环衍生物。

In healthy young adults, after infusion of 1 g IV radiolabeled ertapenem, the plasma radioactivity consists predominantly (94%) of ertapenem. The major metabolite of ertapenem is the inactive ring-opened derivative formed by hydrolysis of the beta-lactam ring.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

温和的、短暂的、无症状的血清转氨酶水平升高在大约5%的接受静脉注射厄他培南5至14天的患者中出现。这些异常通常是自限性的且无症状。在它上市的有限时间内，没有报告出现黄疸的肝炎病例。尽管如此，已经有一些关于其他碳青霉烯类药物在治疗期间或治疗结束后不久出现的胆汁淤积性黄疸的案例。发病的潜伏期在1到3周内，酶升高的模式通常是胆汁淤积性的。可能出现免疫过敏特征，但自身抗体罕见。病程通常是自限性的，但至少已经报告了一例与碳青霉烯类药物相关的消失性胆管综合征。厄他培南和其他碳青霉烯类药物尚未与急性肝衰竭的病例相关联。

Mild, transient, asymptomatic elevations in serum aminotransferase levels occur in about 5% of patients receiving parenteral ertapenem for 5 to 14 days. These abnormalities are usually self-limited and asymptomatic. In the limited period that it has been available, no cases of hepatitis with jaundice have been reported. Nevertheless, several instances of cholestatic jaundice arising during or shortly after therapy have been reported with other carbapenems. The latency to onset has been within 1 to 3 weeks and the pattern of enzyme elevations is usually cholestatic. Immunoallergic features can occur but autoantibodies are rare. The course is usually self-limiting, but at least one case of vanishing bile duct syndrome related to a carbapenem has been reported. Ertapenem and other carbapenems have not been linked to cases of acute liver failure.

来源:LiverTox

毒理性

• 药物性肝损伤

药物名称：厄他培南

Compound:ertapenem

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：模糊的药物性肝损伤关注

DILI Annotation:Ambiguous 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

厄他培南，用1%利多卡因盐酸注射液，美国药典（不含肾上腺素的生理盐水）重新配制后，在推荐剂量1克下通过肌肉注射给药几乎完全吸收。平均生物利用度约为90%。在每日1克肌肉注射给药后，平均血浆峰浓度（Cmax）在大约2.3小时（Tmax）达到。

Ertapenem, reconstituted with 1% lidocaine HCl injection, USP (in saline without epinephrine), is almost completely absorbed following intramuscular (IM) administration at the recommended dose of 1 g. The mean bioavailability is approximately 90%. Following 1 g daily IM administration, mean peak plasma concentrations (Cmax) are achieved in approximately 2.3 hours (Tmax).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

厄他培南与人类血浆蛋白高度结合，主要是白蛋白。在健康的年轻成年人中，随着血浆浓度的增加，厄他培南的蛋白结合率会降低，从大约100微克（ug）/毫升的血浆浓度时约95%结合，到大约300 ug/mL的血浆浓度时约85%结合。

Ertapenem is highly bound to human plasma proteins, primarily albumin. In healthy young adults, the protein binding of ertapenem decreases as plasma concentrations increase, from approximately 95% bound at an approximate plasma concentration of <100 micrograms (ug)/mL to approximately 85% bound at an approximate plasma concentration of 300 ug/mL.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

厄他培南在成人中的稳态表观分布容积（Vss）大约为0.12升/千克，在3个月至12岁的儿科患者中大约为0.2升/千克，在13至17岁的儿科患者中大约为0.16升/千克。

The apparent volume of distribution at steady state (Vss) of ertapenem in adults is approximately 0.12 liter/kg, approximately 0.2 liter/kg in pediatric patients 3 months to 12 years of age and approximately 0.16 liter/kg in pediatric patients 13 to 17 years of age.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

5名患有骨盆感染并在分娩后5至14天内接受静脉滴注治疗的哺乳期妇女（治疗期为3-10天），在最后一次1克剂量治疗后的连续5天内，每天随机时间点测量其乳汁中厄他培南的浓度。在所有5名妇女停药后24小时内，乳汁中厄他培南的浓度范围为小于0.13（定量下限）至0.38微克/毫升；未评估峰值浓度。在停药后第5天，4名妇女的乳汁中厄他培南的水平已检测不到，1名妇女的乳汁中厄他培南水平低于定量下限（小于0.13微克/毫升）。

The concentration of ertapenem in breast milk from 5 lactating women with pelvic infections (5 to 14 days postpartum) was measured at random time points daily for 5 consecutive days following the last 1 g dose of intravenous therapy (3-10 days of therapy). The concentration of ertapenem in breast milk within 24 hours of the last dose of therapy in all 5 women ranged from <0.13 (lower limit of quantitation) to 0.38 ug/mL; peak concentrations were not assessed. By day 5 after discontinuation of therapy, the level of ertapenem was undetectable in the breast milk of 4 women and below the lower limit of quantitation (<0.13 ug/mL) in 1 woman.

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

应用

厄他培南适用于治疗由以下敏感菌株引起的中度至重度感染：

• 继发性腹腔感染：大肠埃希菌、梭状芽孢杆菌、迟缓真杆菌、消化链球菌属、脆弱拟杆菌、吉氏拟杆菌、卵形拟杆菌或多形拟杆菌引起。
• 复杂性皮肤及附属器感染：金黄色葡萄球菌（仅对甲氧西林敏感株）、化脓性链球菌、大肠埃希菌、消化链球菌属引起。
• 社区获得性肺炎：肺炎链球菌（仅青霉素敏感株，包括合并菌血症的病例）、流感嗜血杆菌（仅?-内酰胺酶阴性株）或卡他莫拉球菌引起。
• 复杂性尿道感染，包括肾盂肾炎：大肠埃希菌或肺炎克雷白氏杆菌引起。
• 急性盆腔感染，包括产后子宫内膜炎、流产感染和妇产科术后感染：无乳链球菌、大肠埃希菌、脆弱拟杆菌、不解糖卟啉单胞菌、消化链球菌属或双路普雷沃氏菌属引起。
• 菌血症。

研究表明，厄他培南在治疗复杂性尿道感染方面比头孢曲松更有效，且治疗费用更低。

不良反应

使用该药物后可能出现以下不良反应：腹泻、恶心、呕吐等胃肠道反应；静脉炎；头痛；女性阴道炎。丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）和碱性磷酸酶（ALP）水平升高，肌酐值也有可能上升。据报道，使用该药物的患者癫痫发生率为0.5%。

厄他培南可能导致严重的中枢神经系统不良反应，在合并有高风险因素的情况下，医务人员应避免使用或密切监测患者的不良反应，并在必要时停药并给予对症治疗。对于肾功能不全患者，临床药师需特别关注药物剂量调整及不良反应的管理，以减少其给患者带来的危害。

药代动力学

静脉注射1g厄他培南后30分钟内达到血药浓度峰值（Cmax）为137.0 mg/L；2g剂量的Cmax为255.9 mg/L。肌注1g后生物利用度约为90%，达峰时间为2.3小时，Cmax为67 mg/L。该药物与血浆蛋白结合率为92%-95%，在浓度较低时结合率较高。

主要经肾脏排泄，其血浆半衰期约为4.3-4.6小时。静脉注射1g同位素标记的厄他培南后，尿液中药物排出量为80%，胆汁中药物排出量为10%；其中尿液中占40%为原形药物，其余为代谢产物。

反应信息

• 作为反应物：
  描述：

  厄他培南 在 OXA-48 carbapenemase 作用下， 以 aq. phosphate buffer 、 重水 为溶剂， 反应 0.37h， 生成 (2S,3R)-2-((1S,2R)-1-Carboxy-2-hydroxypropyl)-4-(((3S,5S)-5-((3-carboxyphenyl)carbamoyl)pyrrolidin-3-yl)thio)-3-methyl-3,4-dihydro-2H-pyrrole-5-carboxylic acid
  参考文献：
  名称：

  β-内酰胺酶的新机制：D 类酶通过内酯形成降解 1β-甲基碳青霉烯类。

  摘要：

  β-内酰胺酶威胁着碳青霉烯类的临床应用，碳青霉烯类被认为是最后的抗生素。丝氨酸碳青霉烯酶催化的经典机制是通过酰基酶中间体的水解进行的。我们表明，D 类 β-内酰胺酶还通过前所未有地形成碳青霉烯衍生的 β-内酯来降解临床使用的 1β-甲基取代的碳青霉烯类。β-内酯的形成是由碳青霉烯羟乙基侧链对酰基酶中间体的酯羰基的亲核攻击引起的。碳青霉烯类衍生的内酯产品抑制丝氨酸 β-内酰胺酶（特别是 D 类）和金属-β-内酰胺酶。这些结果定义了 D 类碳青霉烯酶的新机制，其中不需要水解水分子。

  DOI：

  10.1002/anie.201711308
• 作为产物：
  描述：

  4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]-heptane-2-carboxylate 在 4-二甲氨基吡啶 、 palladium 10% on activated carbon 氢气 、 碳酸氢钠 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 水 、 乙腈 为溶剂， -10.0~10.0 ℃ 、827.39 kPa 条件下， 生成 厄他培南
  参考文献：
  名称：

  Improved process for the preparation of carbapenem using carbapenem intermediates and recovery of carbapenem

  摘要：

  公开号：

  EP2388261B1

文献信息

• [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。
• METALLO-BETA-LACTAMASE INHIBITORS
  申请人：Merck Sharp & Dohme Corp.

  公开号：US20160333021A1

  公开（公告）日：2016-11-17

  The present invention relates to compounds of formula (I) that are metallo-β-lactamase inhibitors, the synthesis of such compounds, and the use of such compounds for use with β-lactam antibiotics for overcoming resistance.

  本发明涉及式(I)的化合物，这些化合物是金属β-内酰胺酶抑制剂，以及这些化合物的合成和与β-内酰胺类抗生素一起用于克服耐药性的用途。