纳美芬 | 55096-26-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 菲及其衍生物
• 中文名称: 纳美芬
• 中文别名: (5Α)-17-(环丙基甲基)-4,5-环氧-6-亚甲基吗啡喃-3,14-二醇；盐酸纳美芬
• 英文名称: nalmefene
• 英文别名: (4R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-7-methylidene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,9-diol
• CAS: 55096-26-9
• 化学式: C₂₁H₂₅NO₃
• 分子量: 339.434
• InChiKey: WJBLNOPPDWQMCH-MBPVOVBZSA-N

物化性质

• 熔点：
  182-185?C
• 沸点：
  507.9±50.0 °C(Predicted)
• 密度：
  1.38±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（轻微）、二氯甲烷（轻微）、DMSO（轻微）
• 颜色/状态：
  Crystals from ethyl acetate
• 蒸汽压力：
  5.7X10-14 mm Hg at 25 °C (est)
• 稳定性/保质期：

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

• 解离常数：
  pKa1 = 8.38 (amine); pKa2 = 10.00 (phenol) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  25
• 可旋转键数：
  2
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  52.9
• 氢给体数：
  2
• 氢受体数：
  4

ADMET

代谢

纳美芬在肝脏中被广泛代谢，主要通过由UGT2B7和UGT1A3以及UGT1A8介导的葡萄糖醛酸苷结合反应，主要代谢物是药理学上不活跃的纳美芬3-O-葡萄糖醛酸苷。纳美芬还会代谢成微量的N-脱烷基代谢物，这种代谢物的药理活性很小。纳美芬可以通过CYP3A4/5介导的脱烷基反应形成纳洛美芬。纳洛美芬可以进一步转化为纳洛美芬3-O-葡萄糖醛酸苷和纳洛美芬3-硫酸盐，这些通常是不活跃的代谢物。纳美芬也可以通过CYP3A4/5介导的硫酸化反应形成纳美芬3-O-硫酸盐，这种代谢物保留了一些药理活性。然而，纳美芬3-O-硫酸盐在血液中的浓度不到纳美芬的10%；因此，它不太可能是纳美芬药理活性的主要贡献者。一些受试者的血浆浓度-时间曲线表明，纳美芬可能经历肠肝循环。

Nalmefene is extensively metabolized by the liver, primarily by glucuronide conjugation mainly mediated by UGT2B7 and UGT1A3 and UGT1A8 to a lesser extent. The major metabolite is pharmacologically inactive nalmefene 3-O-glucuronide. Nalmefene is also metabolized to trace amounts of an N-dealkylated metabolite, which has minimal pharmacological activity. Nalmefene can undergo dealkylation mediated by CYP3A4/5 to form nornalmefene. Nornalmefene can be further converted to nornalmefene 3-O-glucuronide and nornalmefene 3-sulfate, which are generally inactive metabolites. Nalmefene can also undergo CYP3A4/5-mediated sulfation to form nalmefene 3-O-sulfate, which retains some pharmacological activity. However, nalmefene 3-O-sulfate is present in the circulation in less than 10% of that of nalmefene; thus, it is unlikely to be a major contributor to the pharmacological activity of nalmefene. The plasma concentration-time profile in some subjects suggests that nalmefene undergoes enterohepatic recycling.

来源:DrugBank

代谢

纳美芬通过肝脏代谢，主要是通过葡萄糖醛酸苷结合，并通过尿液排出。纳美芬还代谢成微量的N-脱烷基代谢物。纳美芬葡萄糖醛酸苷是无效的，而N-脱烷基代谢物具有最小的药理活性。...某些受试者的血浆浓度-时间曲线表明，纳美芬经历肠肝循环。

Nalmefene is metabolized by the liver, primarily by glucuronide conjugation, and excreted in the urine. Nalmefene is also metabolized to trace amounts of an N-dealkylated metabolite. Nalmefene glucuronide is inactive and the N-dealkylated metabolite has minimal pharmacological activity. ... The plasma concentration-time profile in some subjects suggests that nalmefene undergoes enterohepatic recycling.

来源:Hazardous Substances Data Bank (HSDB)

代谢

使用体外和体内方法研究了纳美芬在大鼠和狗体内的处置情况。通过将纳美芬与肝微粒体一起孵化，获得了体外代谢物轮廓，并检测生物流体以分析体内代谢物。使用高效液相色谱（hplc）、与合成标准的共相色谱或液相色谱/质谱（LC/MS）对代谢物进行了表征。在大鼠中，通过静脉推注给予纳美芬后，获得了组织分布和代谢物血浆浓度-时间数据。结果表明，从肝微粒体孵化中，纳美芬的主要I相代谢物是去烷基化代谢物，即诺纳美芬。在大鼠和狗中，代谢物的产生量是大鼠远大于狗。在体内，诺纳美芬葡萄糖苷酸是大鼠尿中的主要代谢物，而在狗尿中占主导地位的是纳美芬葡萄糖苷酸。在静脉推注给予^14C-纳美芬后24小时内，大鼠排泄物和组织中回收了超过90%的放射性剂量，没有明显的器官特异性放射性滞留。对大鼠血浆代谢物数据的药代动力学分析表明，纳美芬和诺纳美芬的终末半衰期相近（大约1小时）。然而，诺纳美芬的Cmax和AUC不超过相应纳美芬值的7%。

The disposition of nalmefene in rat and dog was studied using in vitro and in vivo methodology. In vitro metabolite profiles were obtained following incubation of nalmefene with liver microsomes and biological fluids were assayed to profile in vivo metabolites. Characterization of metabolites was accomplished using hplc, co-chromatography with synthetic standards, or LC/MS. In rat, tissue distribution and metabolite plasma concentration-time data were obtained following intravenous bolus dosing of nalmefene. The results indicate that the primary phase I metabolite of nalmefene from liver microsome incubations was the N-dealkylated metabolite, nornalmefene. Quantitative metabolite production was rat >> dog. In vivo, nornalmefene glucuronide was the major metabolite in rat urine, whereas nalmefene glucuronide(s) were predominant in dog urine. More than 90% of the radioactive dose was recovered in the rat excreta and tissues 24 hr after an intravenous bolus dose of 14C-nalmefene, with no apparent organ-specific retention of radioactivity. Pharmacokinetic analysis of the rat plasma metabolite data indicated that terminal half-lives for nalmefene and nornalmefene were comparable (approximately 1 hr). However, Cmax and AUC of nornalmefene were < or = 7% that of corresponding nalmefene values.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

治疗剂量的纳美芬并未与血清酶水平升高或特异质急性、临床上明显的肝损伤相关。纳美芬在肝脏中广泛代谢，但主要是通过葡萄糖醛酸化而不是转化为不同的代谢物。阿片类药物过量的患者通常有基础性慢性肝病，如酒精性肝病、乙型或丙型肝炎，但纳美芬治疗似乎并未加剧这些状况。 可能性评分：E（不太可能是临床上明显肝损伤的原因）。 药物类别：阿片受体拮抗剂；另见物质滥用治疗剂 同类其他药物：纳洛戈尔、纳洛酮、纳曲酮

Therapy with nalmefene has not been linked to serum enzyme elevations or to idiosyncratic acute, clinically apparent liver injury. Nalmefene is extensively metabolized in the liver, but largely by glucuronidation rather than transformation to a different metabolite. Patients with opioid overdose often have underlying chronic liver diseases such as alcoholic liver disease, hepatitis B or C, but treatment with nalmefene does not appear to exacerbate those conditions. Likelihood score: E (unlikely cause of clinically apparent liver injury). Drug Class: Opioid Antagonists; see also Substance Abuse Treatment Agents Other Drugs in the Class: Naloxegol, Naloxone, Naltrexone

来源:LiverTox

毒理性

• 相互作用

临床前研究表明，氟马西尼和纳美芬都能在动物中诱发癫痫。在一项针对啮齿类动物的研究中，同时给予氟马西尼和纳美芬所引发的癫痫数量少于预期，这是基于每种药物单独作用的预期效果。根据这些数据，预计这两种药物联合使用不会产生不良反应，但医生应保持警惕，注意这些类药物可能引发的癫痫风险。

Preclinical studies have shown that both flumazenil and nalmefene can induce seizures in animals. The coadministration of both flumazenil and nalmefene produced fewer seizures than expected in a study in rodents, based on the expected effects of each drug alone. Based on these data, an adverse interaction from the coadministration of the two drugs is not expected, but physicians should remain aware of the potential risk of seizures from agents in these classes.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中毒物清除。如果患者停止呼吸，开始人工呼吸，最好使用需求阀复苏器、袋阀面罩装置或口袋面罩，按训练操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果发生呕吐，让患者前倾或置于左侧（如果可能的话，头部向下）以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗帮助。 /毒物A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，协助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要，进行治疗……。监测休克，如有必要，进行治疗……。预期癫痫发作，如有必要，进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（NS）持续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能够吞咽、有强烈的干呕反射且不流口水，则用温水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒药A和B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 高级治疗：对于无意识、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用带阀口罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注5%葡萄糖水（D5W）/SRP: "保持开放"，最小流量/。如果出现低血容量的迹象，使用0.9%生理盐水（NS）或乳酸林格液。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。使用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。/毒物A和B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

在单次口服18.06毫克后，纳美芬被迅速吸收，其绝对口服生物利用度为41%。Cmax（最高血药浓度）为16.5 ng/mL，Tmax（达到最高血药浓度的时间）大约为1.5小时。暴露量（AUC，药时曲线下面积）为131 ng·h/mL。高脂肪餐使AUC增加了30%，Cmax增加了50%，并将Tmax推迟了30分钟；然而，这在临床上可能没有显著意义。纳美芬在静脉注射0.5毫克到2毫克时表现出剂量比例的药代动力学。肌内注射后的Tmax为2.3 ± 1.1小时，皮下注射后的Tmax为1.5 ± 1.2小时。在紧急情况下，1毫克剂量的治疗血药浓度可能在5到15分钟内达到。肌内和皮下给药的吸收速度存在变异性。

Nalmefene is rapidly absorbed after a single oral administration of 18.06 mg with an absolute oral bioavailability of 41%. The Cmax was 16.5 ng/mL and Tmax was approximately 1.5 hours. The exposure (AUC) was 131 ng x h/mL. High-fat meal increased the AUC by 30% and Cmax by 50% and delayed Tmax by 30 min; however, this is unlikely of clinical significance. Nalmefene exhibits dose-proportional pharmacokinetics following intravenous administration of 0.5 mg to 2 mg. Tmax was 2.3 ± 1.1 hours following intramuscular administration and 1.5 ± 1.2 hours following subcutaneous administration. Therapeutic plasma concentrations are likely to be reached within 5 to 15 minutes after a 1 mg dose in an emergency. There is variability in the speed of absorption for intramuscular and subcutaneous dosing.

来源:DrugBank

吸收、分配和排泄

• 消除途径

肾脏排泄是纳美芬及其代谢物的主要消除途径。大约54%的总剂量以纳美芬3-O-葡萄糖苷酸的形式通过尿液排出。不到3%的剂量以纳美芬或其他代谢物的形式排出。大约17%的剂量通过粪便排出。

Renal excretion is the main route of elimination for nalmefene and its metabolites. About 54% of the total dose is excreted in the urine as nalmefene 3-O-glucuronide. Less than 3% of the dose is excreted as nalmefene or other metabolites. About 17% of the dose is excreted in the feces.

来源:DrugBank

吸收、分配和排泄

• 分布容积

在给予1毫克静脉注射剂量后，纳美芬迅速分布。中心分布的表观体积（Vc）和稳态时的分布体积（Vdss）分别为3.9 ± 1.1 L/kg 和 8.6 ± 1.7 L/kg。纳美芬容易穿过血脑屏障。

Following a 1 mg parenteral dose, nalmefene was rapidly distributed. The apparent volumes of distribution centrally (V_c) and at steady-state (V_dss) are 3.9 ± 1.1 L/kg and 8.6 ± 1.7 L/kg, respectively. Nalmefene readily crosses the blood-brain barrier.

来源:DrugBank

吸收、分配和排泄

• 清除

纳美芬的口服清除率（CL/F）估计为169 L/h。在静脉注射1毫克纳美芬后，纳美芬的系统性清除率为0.8 ± 0.2 L/小时/公斤，肾清除率为0.08 ± 0.04 L/小时/公斤。

The oral clearance of nalmefene (CL/F) was estimated as 169 L/h. Following intravenous administration of 1 mg nalmefene, the systemic clearance of nalmefene was 0.8 ± 0.2 L/hr/kg and the renal clearance was 0.08 ± 0.04 L/hr/kg.

来源:DrugBank

吸收、分配和排泄

纳美芬在12名男性志愿者中通过肌肉注射或皮下给药后，与静脉纳美芬相比，完全具有生物利用度。肌肉注射和皮下给药途径的相对生物利用度分别为101.5% +/- 8.1%（平均值 +/- 标准差）和99.7% +/- 6.9%。

Nalmefene was completely bioavailable following intramuscular or subcutaneous administration in 12 male volunteers relative to intravenous nalmefene. The relative bioavailabilities of intramuscular and subcutaneous routes of administration were 101.5% +/-8.1% (Mean +/- SD) and 99.7% +/-6.9%, respectively.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xi
• 安全说明：
  S26,S36
• 危险类别码：
  R36/37/38
• WGK Germany：
  3

制备方法与用途

化学性质：乙酸乙酯结晶，熔点为188～190℃。

用途：鸦片受体拮抗剂。

生产方法：通过将纳酮(Naltrexone[16590-41-3])与三苯基甲基溴化镁进行Wittig反应，即可得到纳美芬。