纳洛酮 | 465-65-6

• 物质功能分类: 原料药 - 专科用药 - 解毒药
• 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: 纳洛酮
• 中文别名: (5alpha)-3,14-二羟基-17-丙-2-烯-1-基-4,5-环氧吗啡烷-6-酮
• 英文名称: Naloxone
• 英文别名: (-)-17-allyl-4,5α-epoxy-3,14-dihydroxy-6-morphinan-6-one；(5α)-4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one；naloxone hydrochloride；(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-prop-2-enyl-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one
• CAS: 465-65-6
• 化学式: C₁₉H₂₁NO₄
• 分子量: 327.38
• InChiKey: UZHSEJADLWPNLE-GRGSLBFTSA-N

物化性质

• 熔点：
  184° (Lewenstein), 177-178° (Sankyo Co.)
• 比旋光度：
  D20 -194.5° (c = 0.93 in CHCl3)
• 沸点：
  465.27°C (rough estimate)
• 密度：
  1.2223 (rough estimate)
• 闪点：
  9℃
• 溶解度：
  氯仿（微溶、加热、超声处理）、DMSO（微溶）、甲醇（微溶）、
• 物理描述：
  Solid
• 颜色/状态：
  Crystals from ethyl acetate
• 蒸汽压力：
  4.25X10-11 mm Hg at 25 °C (est)
• 旋光度：
  Specific optical rotation: -194.5 deg at 20 °C/D (c = 0.93 in HCl)
• 分解：
  When heated to decomposition it emits toxic fumes of /nitrogen oxides/.
• 解离常数：
  pKa1 = 7.84 (amine); pKa2 = 10.07 (phenol); pKa3 = 13.58 (hydroxy) (est)
• 碰撞截面：
  171.8 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  70
• 氢给体数：
  2
• 氢受体数：
  5

ADMET

代谢

纳洛酮主要通过葡萄糖醛酸化反应形成纳洛酮-3-葡萄糖醛酸苷。纳洛酮也可以N-脱烷基化成为去甲氧吗啡，或者经过6-酮还原成为纳洛醇。

Naloxone primarily undergoes glucuronidation to form naloxone-3-glucuronide. Naloxone is also N-dealkylated to noroxymorphone or undergoes 6-keto reduction to naloxol.

来源:DrugBank

代谢

纳洛酮在肝脏中迅速代谢，主要是通过与葡萄糖醛酸结合。主要代谢物是纳洛酮-3-葡萄糖苷酸。纳洛酮还发生N-脱烷基化和6-酮基团的还原，然后进行结合反应。

Naloxone is rapidly metabolized in the liver, principally by conjugation with glucuronic acid. The major metabolite is naloxone-3-glucuronide. Naloxone also undergoes N-dealkylation and reduction of the 6-keto group followed by conjugation.

来源:Hazardous Substances Data Bank (HSDB)

代谢

产生N-烯丙基-7,8-二氢-14-羟基诺莫啡，7,8-二氢-14-羟基诺莫啡酮；Weinstein, SH, Pfeffer, M, Schor, JM, Indindoli, L, & Mintz, M，药物科学杂志，60, 1567 (1971)。在人中产生纳洛酮-3-β-D-葡萄糖醛酸苷；Fujimoto, JM，药物实验治疗杂志，168, 180(1969)。/来自表格/

Yields N-allyl-7,8-dihydro-14-hydroxynormorphine, 7,8-dihydro-14-hydroxynormorphinone in man; Weinstein, SH, Pfeffer, M, Schor, JM, Indindoli, L, & Mintz, M, J Pharm Sci, 60, 1567 (1971). Yields naloxone-3-beta-d-glucuronide in man; Fujimoto, JM, J Pharmac Exp Ther, 168, 180(1969). /From table/

来源:Hazardous Substances Data Bank (HSDB)

代谢

氧化去烯基化、6-酮基团的还原以及葡萄糖苷酸化在人体内发生。

... Oxidative N-deallylation, redn of 6-keto-group, and glucuronidation occur in man.

来源:Hazardous Substances Data Bank (HSDB)

代谢

纳洛酮-3-葡萄糖苷酸（主要），3-硫酸盐（次要），纳洛醇和结合型纳洛醇（次要），7,8-二氢-14-羟基诺莫啡，7,8-二氢-14-羟基诺莫啡及其结合物被显示为纳洛酮的代谢物。此外，还获得了两个极性羟基化代谢物（羟基化可能发生在17-侧链或芳香核的位置2）的初步证据。7,8-二氢-14-羟基诺莫啡酮和2个极性代谢物也在大脑中观察到。

... Naloxone-3-glucuronide (major), 3-sulfate (minor), naloxol and conjugated naloxol (minor), 7,8-dihydro-14-hydroxynormorphine, 7,8-dihydro-14-hydroxynormorphine and their conjugates were shown to be the metabolites of naloxone. In addition, tentative evidence was obtained for two polar hydroxylated metabolites (with hydroxylation presumably in the 17-side chain or in position 2 of the aromatic nucleus). 7,8-Dihydro-14-hydroxynormorphinone and 2-polar metabolites were also observed in brain. ...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

鉴别人和使用：纳洛酮由晶体组成。纳洛酮盐酸盐用于完全或部分逆转由天然和合成阿片类药物（包括人类和兽医病例）引起的阿片类药物抑郁，包括呼吸抑制。它还可能作为辅助剂，用于提高感染性休克治疗中的血压。野生动物使用的制剂（Trexonil）浓度更高，用于逆转野生动物的镇静状态。人类暴露和症状：与纳洛酮使用相关的不良反应包括癫痫发作、严重高血压、低血压和/或心动过缓。总共1.2毫克静脉注射给非吸毒者，分别在11、22和33分钟以0.2、0.4和0.6毫克的剂量给药，导致瞳孔缩小、核心体温降低和收缩压下降。纳洛酮引起的急性肺水肿是一种极其罕见但致命的并发症。内源性阿片类药物似乎在某些高血压患者的血压调节中发挥作用，因此像纳洛酮这样的阿片类药物拮抗剂必须谨慎给予这些人。纳洛酮给药后，儿童会出现呼吸频率、心率和血压的中度增加，但发展成更严重并发症的情况罕见。纳洛酮在体外人淋巴细胞染色体畸变试验中呈弱阳性。纳洛酮可能会影响人类免疫系统的某些功能，但其作用是暂时的。动物研究：将纳洛酮注射到大鼠的内侧隔核中，以剂量依赖性方式显著增加了海马的ACh释放。还发现，注射纳洛酮的大鼠表现出活动能力增加，偶尔出现行为性癫痫。在大鼠皮下注射100毫克/千克/天，连续3周，仅在注射后产生暂时的流涎和部分上睑下垂。从大鼠怀孕第17天开始给药，显著增加了新生儿死亡率。纳洛酮给药略微减缓了体重增加。纳洛酮在Ames致突变试验中呈弱阳性，在体外中国仓鼠V79细胞HGPRT致突变试验和体内大鼠骨髓染色体畸变研究中呈阴性。

IDENTIFICATION AND USE: Naloxone is composed of crystals. Naloxone hydrochloride is used for the complete or partial reversal of opioid depression, including respiratory depression, induced by natural and synthetic opioids (both human and veterinary cases). It may also be useful as an adjunctive agent to increase blood pressure in the management of septic shock. A formulation for wildlife use (Trexonil) is more concentrated and used to reverse tranquilization in wild animals. HUMAN EXPOSURE AND SYMPTOMS: Adverse effects associated with naloxone use have included seizures, severe hypertension, and hypotension and/or bradycardia. A total of 1.2 mg administered intravenously as 0.2, 0.4, and 0.6 mg at 11, 22, and 33 minutes respectively to nonaddicts caused miosis, decreased core temperature, and systolic blood pressure. Naloxone-induced acute pulmonary edema is an extremely rare but lethal complication. Endogenous opioids appear to regulate blood pressure in some hypertensive patients and opiate antagonists such as naloxone must be administered with caution to these individuals. Moderate increases in respiratory rate, heart rate, and blood pressure occur after naloxone administration to children, but development of more serious complications is rare. Naloxone was weakly positive in the in vitro human lymphocyte chromosome aberration test. Naloxone may affect some functions of the immune system in humans, but its action is transient. ANIMAL STUDIES: The injection of naloxone into the medial septal nucleus of rats produced a marked increase in hippocampal ACh release in a dose-dependent manner. It was also found that rats given an injection of naloxone showed an increase in motor activity and occasionally exhibited behavioral seizures. Subcutaneous injection of 100 mg/kg/day in rats for 3 weeks produced only transient salivation and partial ptosis following injection. Administration of naloxone to rats from day 17 of pregnancy significantly increased neonatal death. Body weight increase was slightly retarded by administration of naloxone. Naloxone was weakly positive in the Ames mutagenicity test and was negative in the in vitro Chinese hamster V79 cell HGPRT mutagenicity assay and the in vivo rat bone marrow chromosome aberration study.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

使用纳洛酮治疗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联。患有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，但纳洛酮治疗似乎并未加剧这些状况。纳洛酮在肝脏中广泛代谢，但主要是通过葡萄糖醛酸结合然后随尿液排出。 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：阿片类拮抗剂；另见物质滥用治疗剂 同类其他药物：纳美芬；纳洛戈隆，纳曲酮

Therapy with naloxone has not been linked to serum enzyme elevations or to idiosyncratic acute, clinically apparent liver injury. Patients with opioid overdose often have underlying chronic liver diseases such as alcoholic liver disease, hepatitis B or C, but treatment with naloxone does not appear to exacerbate those conditions. Naloxone is extensively metabolized in the liver, but largely by conjugation with glucuronide followed by its urinary excretion. 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: Nalmefene; Naloxegol, Naltrexone

来源:LiverTox

毒理性

• 药物性肝损伤

纳洛酮

Compound:naloxone

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注释：无 DILI（药物性肝损伤）担忧

DILI Annotation:No-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：无匹配

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

一个鼻内剂量的纳洛酮的生物利用度为42-47%。8毫克的鼻内纳洛酮剂量达到12.3-12.8纳克/毫升的Cmax，Tmax为0.25小时，AUC为16.7-19.0小时*纳克/毫升。0.4毫克肌肉注射剂量达到0.876-0.910纳克/毫升的Cmax，Tmax为0.25小时，AUC为1.94-1.95小时*纳克/毫升。2毫克静脉注射剂量达到26.2纳克/毫升的Cmax，AUC为12.8小时*纳克/毫升。

An intranasal dose of naloxone is 42-47% bioavailable. An 8 mg dose of nasal naloxone reaches a Cmax of 12.3-12.8 ng/mL, with a Tmax of 0.25 hours, and an AUC of 16.7-19.0 h\*ng/mL. A 0.4 mg intramuscular dose reaches a Cmax of 0.876-0.910 ng/mL, with a Tmax of 0.25 hours, and an AUC of 1.94-1.95 h\*ng/mL. A 2 mg intravenous dose reaches a Cmax of 26.2 ng/mL with an AUC of 12.8 h\*ng/mL.

来源:DrugBank

吸收、分配和排泄

• 消除途径

口服或静脉给药后，纳洛酮在6小时内约有25-40%通过尿液排出，24小时内达到50%，72小时内达到60-70%。尿液中可以检测到纳洛酮的代谢物纳洛酮-3-葡萄糖苷酸、去甲氧吗啡和纳洛醇。

After oral or intravenous administration, naloxone is 25-40% eliminated in the urine within 6 hours, 50% in 24 hours, and 60-70% in 72 hours. The metabolites naloxone-3-glucuronide, noroxymorphone, and naloxol are all detected in the urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

纳洛酮的分布容积为200升。纳洛酮迅速分布到组织中。它还可以穿过胎盘和血脑屏障。

The volume of distribution of naloxone is 200 L. Naloxone distributes into tissues rapidly. It can also cross the placenta and blood-brain barrier.

来源:DrugBank

吸收、分配和排泄

• 清除

纳洛酮的清除率为2500升/天。

The clearance of naloxone is 2500 L/day.

来源:DrugBank

吸收、分配和排泄

纳洛酮在体内分布迅速，在大脑、肾脏、脾脏、骨骼肌、肺和心脏中含量较高。该药物也容易穿过胎盘。

Naloxone is distributed rapidly throughout the body with high levels found in the brain, kidneys, spleen, skeletal muscle, lung, and heart. The drug also readily crosses the placenta.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  F,T
• 安全说明：
  S16,S36/37,S45,S7
• 危险类别码：
  R11,R23/24/25,R39/23/24/25
• WGK Germany：
  2,3
• 海关编码：
  2939190000

制备方法与用途

背景概述

纳洛酮于20世纪60年代合成并逐渐应用于临床。近年来，随着研究深入，内源性阿片肽尤其是β-内啡肽在多种疾病病理生理过程中的作用进一步明确。作为阿片受体的特异性拮抗剂，纳洛酮能有效阻断和逆转内源性阿片肽的毒性作用，并广泛应用于各种急性中毒、肝性脑病、脑卒中、颅脑和脊髓损伤、休克、新生儿窒息、心肺复苏、眩晕症、阿片类药物急性中毒的解毒及其依赖患者的诊断与治疗、麻醉后的催醒等。随着对其药理机制研究的不断深入，纳洛酮的应用领域也不断拓展。

纳洛酮（Naloxone）又名丙烯吗啡，是一种羟二氢吗啡酮衍生物，其化学结构类似于吗啡，是特异性的吗啡受体拮抗剂，对阿片样物质及内源性阿片样物质、内啡肽和脑啡肽具有特异性拮抗作用。β-内啡肽（β-endorphin，β-EP）在内源性阿片受体类似物中活性最强，并在痛觉感知、镇痛、垂体激素分泌、心血管活性及呼吸调节等方面发挥作用。在脑梗死、休克、脑缺氧及应激情况下，脑内β-内啡肽释放增加。纳洛酮通过对内啡肽的拮抗作用而发挥兴奋中枢神经、促进呼吸和抑制中枢迷走神经的作用，从而使血中去甲肾上腺素和肾上腺素水平升高，血压上升。

药理作用

纳洛酮是一种纯粹的阿片受体拮抗药，自身并无内在活性，但能竞争性拮抗各类阿片受体，特别是对μ受体有很强的亲和力。盐酸纳洛酮起效迅速，具有强大的拮抗作用，并可逆转阿片激动剂的所有作用（包括镇痛），还具有与阿片受体无关的复苏作用。它可以快速逆转阿片类镇痛药引起的呼吸抑制，引发高度兴奋，增强心血管功能。此外，纳洛酮还具有抗休克作用，不会产生吗啡的依赖性、戒断症状及呼吸抑制。

药代动力学

静注后1～2分钟即可达到最大效应，持续约45分钟；肌注后5～10分钟产生最大效应，持续2.5～3小时。纳洛酮吸收迅速，易通过血脑屏障，代谢快，人血浆半衰期为60～90分钟，主要在肝脏内进行生物转化。

适应症

纳洛酮适用于阿片类药物过量中毒；用于诊断阿片类药物成瘾；应用于吗啡类复合麻醉药术后，解除呼吸抑制、催醒及急性酒精中毒。