胰岛素 | 9004-10-8

• 物质功能分类: 原料药 - 激素及调节内分泌功能类药 - 胰腺激素及其它调节血糖药
• 分子结构分类: 有机化合物 - 有机聚合物 - 多肽
• 中文名称: 胰岛素
• 英文名称: Insulin
• 英文别名: (4S)-4-[[2-[[(1R,6R,12S,15S,18S,21S,24S,27S,30S,33S,36S,39S,42R,47R,50S,53S,56S,59S,62S,65S,68S,71S,74S,77S,80S,83S,88R)-88-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[(2-aminoacetyl)amino]-3-methylpentanoyl]amino]-3-methylbutanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]-6-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-3-amino-2-[[(2S)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-3-methylbutanoyl]amino]-3-oxopropanoyl]amino]-5-oxopentanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-4-methylpentanoyl]amino]-47-[[(1S)-3-amino-1-carboxy-3-oxopropyl]carbamoyl]-53-(2-amino-2-oxoethyl)-62-(3-amino-3-oxopropyl)-77-[(2R)-butan-2-yl]-24,56-bis(2-carboxyethyl)-83-[(1S)-1-hydroxyethyl]-12,71,80-tris(hydroxymethyl)-33,50,65-tris[(4-hydroxyphenyl)methyl]-15-(1H-imidazol-4-ylmethyl)-27-methyl-18,30,36,59,68-pentakis(2-methylpropyl)-7,10,13,16,19,22,25,28,31,34,37,40,49,52,55,58,61,64,67,70,73,76,79,82,85,87-hexacosaoxo-21,39-di(propan-2-yl)-3,4,44,45,90,91-hexathia-8,11,14,17,20,23,26,29,32,35,38,41,48,51,54,57,60,63,66,69,72,75,78,81,84,86-hexacosazabicyclo[72.11.7]dononacontane-42-carbonyl]amino]acetyl]amino]-5-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[(2S)-2-[[(2S)-6-amino-1-[[(1S,2S)-1-carboxy-2-hydroxypropyl]amino]-1-oxohexan-2-yl]carbamoyl]pyrrolidin-1-yl]-3-hydroxy-1-oxobutan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-oxopentanoic acid
• CAS: 9004-10-8
• 化学式: C₂₅₆H₃₈₁N₆₅O₇₇S₆
• 分子量: 5794.0
• InChiKey: YAJCHEVQCOHZDC-QMMNLEPNSA-N

物化性质

• 熔点：
  233 °C
• 密度：
  1.09 g/cm3
• 溶解度：
  可溶于酸性水，pH 2.0:2 mg/mL
• 颜色/状态：
  COLORLESS OR ALMOST COLORLESS IF CONTAINING NOT MORE THAN 100 USP UNITS/ML; STRAW-COLORED IF CONTAINING 500 UNITS
• 稳定性/保质期：
  REGULAR ILETIN HAD 5% LOSS OF POTENCY AFTER STORAGE AT 25 °C FOR 12 MONTHS

计算性质

• 辛醇/水分配系数(LogP)：
  -12.8
• 重原子数：
  404
• 可旋转键数：
  178
• 环数：
  12.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  2450
• 氢给体数：
  78
• 氢受体数：
  89

ADMET

代谢

体外实验表明，有两种系统参与肝脏对胰岛素的降解：(1) 一种被称为谷胱甘肽-胰岛素转移酶的酶，它利用还原型谷胱甘肽来还原二硫键；以及(2) 一种蛋白水解酶，能够将还原并分离的链切割成肽和氨基酸。

IN-VITRO EXPT SUGGESTS 2 SYSTEMS INVOLVED IN DEGRADATION OF INSULIN BY LIVER: (1) ENZYME TERMED GLUTATHIONE-INSULIN TRANSHYDROGENASE, WHICH UTILIZES REDUCED GLUTATHIONE TO REDUCE DISULFIDE BRIDGES; & (2) PROTEOLYTIC ENZYME(S) THAT CLEAVES REDUCED & SEPARATED CHAINS TO PEPTIDES & AMINO ACIDS.

来源:Hazardous Substances Data Bank (HSDB)

代谢

一种能降解胰岛素和胰高血糖素的蛋白水解酶已从大鼠骨骼肌中广泛纯化。

A PROTEOLYTIC ENZYME THAT DEGRADES BOTH INSULIN & GLUCAGON HAS BEEN EXTENSIVELY PURIFIED FROM RAT SKELETAL MUSCLE.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

胰岛素是一种抗糖尿病药物。胰岛素是从猪或牛的兰格汉斯岛β细胞中提取出来，并通过结晶法纯化的。它也可以通过使用大肠杆菌的重组DNA技术生物合成制造，或通过酶修饰猪材料半合成制造。该物质性质：白色或几乎白色的结晶粉末。胰岛素注射液是一种无色或稻草黄色的液体，几乎不含在静置时沉积的固体物质。微溶于水。实际上不溶于酒精、氯仿和醚。溶于稀矿酸溶液，并在碱性氢氧化物溶液中降解。人类暴露：主要风险和靶器官：低血糖是胰岛素过量的主要风险。大脑依赖葡萄糖作为其能量来源，低血糖可能导致昏迷、抽搐甚至死亡。临床效果总结低血糖：低血糖的早期症状包括虚弱、饥饿、眩晕、苍白、出汗、胃部下沉感、心悸、易怒、紧张、头痛和颤抖。症状类似于交感神经刺激。后来，由于神经低血糖，可能出现如抑郁或欣快、无法集中注意力、视力模糊、嗜睡、判断力和自控力丧失以及遗忘等症状。其他特征包括偏瘫、共济失调、心动过速、复视和感觉异常。如果未经治疗，病情会进展为抽搐、昏迷和死亡。在昏迷前期，巴宾斯基反射通常存在。瞳孔通常扩大，但对光有反应。后来瞳孔收缩，不再对光有反应。可能出现低钾血症。低血糖发作的速度取决于所使用的胰岛素制剂。如果血糖浓度大幅下降，也可能发生抽搐。在慢性高血糖的糖尿病患者中，低血糖的症状可能在较高的血糖浓度下发生。少数患者可能在没有先兆症状的情况下发展为低血糖昏迷。其他效果：非特异性局部反应，如过敏反应、脂肪萎缩或硬化和肥大有时发生在注射部位（通常不会对高度纯化的胰岛素造成问题）。禁忌症：绝对：低血糖相对：可能对牛或猪胰岛素发生过敏反应。注意事项：已报告牛和猪胰岛素的免疫反应不同，并且在牛胰岛素更换为猪胰岛素的患者中报告了低血糖。建议小心避免无意中从一种物种的胰岛素更换为另一种物种。在更换为高度纯化的胰岛素时可能需要小心。胰岛素引起的低血糖可能会被酒精、单胺氧化酶抑制剂和普萘洛尔以及其他β受体阻滞剂增强。普萘洛尔可能会掩盖低血糖的症状。任何肾功能恶化或严重肝病的减少都可能减少胰岛素的清除，并可能导致低血糖。进入途径：口服：口服胰岛素没有降糖作用，因为它在胃肠中被灭活。非肠道：胰岛素通过皮下、肌肉或静脉注射给药，只有通过这种途径才可能发生中毒。暴露途径的吸收：胰岛素必须通过SC、IM或IV注射。它被吸收到血液中，皮下胰岛素的血浆胰岛素浓度峰值出现在60-90分钟。如果存在外周血管疾病或吸烟，吸收会变慢，如果患者通过热水浴或紫外线暴露或运动血管扩张，吸收会更快。任何改变给药方式的情况，无论是意外地（意外IM或IV注射）还是故意地（持续皮下胰岛素输注），都可能增强胰岛素的吸收和作用，导致低血糖。在持续输注过程中可能会出现严重低血糖，并且已经报道了几例死亡。胰岛素从注射部位的吸收受到胰岛素脂肪营养不良的影响非常不可预测，快速吸收可能导致低血糖。暴露途径的分布：一部分内源性或外源性胰岛素在血浆中可能与某些蛋白质结合，但大部分似乎以自由激素的形式在血液和淋巴中循环。胰岛素的分布容积接近细胞外液的体积。胰岛素在肝脏和肾脏中被灭活（单次通过约40%）。约10%出现在尿液中。暴露途径的生物半衰期：血浆半衰期为：静脉注射：10分钟；皮下注射：4小时；肌肉注射：2小时。代谢：代谢主要发生在肝脏和肾脏；剂量的10%出现在尿液中。胰岛素通常在肾小球被过滤，然后在近端小管被完全重吸收或破坏。在肾小管功能受损的患者中，尿清除率接近肾小球滤过率。到达肝脏的胰岛素中，有50%在一次通过时被破坏，从未到达全身循环。胰岛素的蛋白降解既发生在细胞表面也在溶酶体中。已经从肌肉中纯化了一种降解胰岛素的蛋白水解酶。一种酶，谷胱甘肽胰岛素转氢酶，利用还原型谷胱甘肽来还原胰岛素的二硫键并产生单独的链，已被涉及。严重的肾功能损害似乎比肝病更能影响循环中胰岛素消失的速度。暴露途径的消除：约10%的药物出现在尿液中。作用方式：毒物动力学：过量的胰岛素引起低血糖。低血糖剥夺大脑依赖于其氧化代谢的底物葡萄糖。在胰岛素昏迷期间，人脑的氧消耗几乎减少了一半。在人类中可能会出现抽搐、昏迷、智力迟钝、偏

IDENTIFICATION: Insulin is antidiabetic drug. Insulin is extracted from beta cells of the islets of Langerhans of pork or beef pancreas and purified by crystallization. It is also made biosynthetical by recombinant DNA technology using Escherichia coli or semisynthetically by enzymatic modification of porcine material. Properties of the substance: white or almost white crystalline powder. Insulin injection is a colorless injection or straw colored liquid practically free from solid matter which deposits on standing. Slightly soluble in water. Practically insoluble in alcohol, chloroform and ether. Soluble in dilute solution of mineral acids and with degradation in solutions of alkali hydroxide. HUMAN EXPOSURE: Main risks and target organs: Hypoglycemia is the main risk of insulin overdose. The brain relies on glucose as its source of energy and hypoglycemia may lead to coma, convulsions and even death. Summary of clinical effects Hypoglycemia: The early symptoms of hypoglycemia are weakness, hunger, giddiness, pallor, sweating, sinking feeling in the stomach, palpitations, irritability, nervousness, headache and tremor. Symptoms resemble those of sympathetic stimulation. Later, symptoms such as depression or euphoria, inability to concentrate, blurring of vision, drowsiness, lack of judgement and self control and amnesia may be present due to neuroglycopenia. Other features are hemiplegia, ataxia, tachycardia, diplopia and paraesthesia. If untreated the condition progresses to convulsions, coma and death. In the precoma stage, Babinski reflex is often present. Pupils are often dilated but react to light. Later pupils are constricted and no longer react to light. Hypokalemia may be present. Speed of onset of hypoglycemia varies with the preparation of insulin used. Convulsions can also occur if the blood glucose concentration falls greatly. In diabetic patients with chronic hyperglycemia, symptoms of hypoglycemia may occur at higher blood glucose concentrations. A few patients may develop hypoglycemic coma without prior warning symptoms. Other effects: Non-specific local reactions such as allergic reactions, atrophy of fat or induration and hypertrophy sometimes occur at the site of injection (usually not a problem with highly purified insulins). Contraindications: Absolute: Hypoglycaemia Relative: Allergic reactions may occur to beef or porcine insulins. Precautions: Differing immunological response to bovine and porcine insulin have been reported and hypoglycaemia has been reported in patients changing from bovine to porcine insulin. Care is recommended to avoid inadvertent change of insulin from one species to another. Care may be necessary in changing over to a highly purified insulin. The hypoglycemia caused by insulin may be enhanced by alcohol, monoamine oxidase inhibitors and propranolol and other beta blockers. Propranolol may mask the symptoms of hypoglycemia. Any deterioration in renal function and severe hepatic disease may reduce insulin clearance and may result in hypoglycemia. Routes of entry: Oral: When taken orally insulin has no hypoglycemic effect since it is inactivated in the gastrointestinal tract. Parenteral: Insulin is administered by subcutaneous, intramuscular or intravenous injections and poisoning can occur only through this route. Absorption by route of exposure: Insulin must be injected SC, IM or IV. It is absorbed into the blood and peak plasma insulin concentration with subcutaneous insulin occurs at 60 - 90 min. Absorption is slower if there is peripheral vascular disease or smoking, and faster if the patient is vasodilated by a hot bath or ultraviolet exposure or exercise. Any changes in mode of administration either accidentally (accidental IM or IV injection) or deliberately (Constant subcutaneous insulin infusion) may potentiate the absorption and action of insulin, leading to hypoglycemia. Severe hypoglycemia may occur during constant infusion and several deaths have been reported. Absorption of insulin from injection site affected by insulin lipodystrophy is very unpredictable and rapid absorption may lead to hypoglycemia. Distribution by route of exposure: A fraction of endogenous or exogenous insulin in plasma may be associated with certain proteins but the bulk appears to circulate in blood and lymph as the free hormone. The volume of distribution of insulin approximates the volume of extracellular fluid. Insulin is inactivated in the liver and kidneys (about 40% in a single passage). About 10% appear in the urine. Biological half-life by route of exposure: The plasma half-life is: intravenous injection: 10 minutes; subcutaneous injection: 4 hours; intramuscular injection: 2 hrs. Metabolism: Metabolism occurs mainly in the liver and kidneys; 10% of the dose appears in the urine. Insulin is normally filtered at the glomeruli and then completely reabsorbed or destroyed at the proximal tubule. In patients with impaired renal tubular function, urinary clearance approaches glomerular filtration rates. 50% of insulin that reaches the liver via the portal vein is destroyed in a single passage, never reaching the general circulation. Proteolytic degradation of insulin occurs both at cell surfaces and in the lysosomes. A proteolytic enzyme that degrades insulin has been purified from muscle. An enzyme, glutathione insulin transhydrogenase, which utilises reduced glutathione to reduce disulfide bridges of insulin and produce separate chains, has been implicated. Severe impairment of renal function appears to affect the rate of disappearance of circulating insulin to a greater extent than does hepatic disease. Elimination by route of exposure: About 10% of the drug appears in urine. Mode of action: Toxicodynamics: Insulin in overdose causes hypoglycaemia. Hypoglycaemia deprives the brain of substrate glucose upon which it is almost exclusively dependent for its oxidative metabolism. During insulin coma, oxygen consumption in the human brain decreases by nearly half. Convulsions, coma, mental retardation, hemiparesis, ataxia, incontinence, aphasia, choreiform movements, and parkinsonism may occur in man. Pharmacodynamics: Insulin binds to a receptor on the surface of the target cell and probably also enters the cell in this state. The receptors vary in number inversely with the insulin concentration to which they are exposed. Teratogenicity: Congenital malformations occurred in 17 of 117 babies born to diabetic mothers taking insulin at the time of conception. Interactions: Alcohol, beta blockers, salicylates, oxytetracycline and monoamine oxidase inhibitors potentiate the hypoglycaemic effects of insulin. Bezafibrate and clofibrate may improve glucose tolerance and have an additive effect. Corticosteroids,corticotrophin, diazoxide, diuretics like bumetanide, furosemide and thiazides and oral contraceptives antagonize the effects of insulin. Lithium may occasionally impair glucose tolerance. ANIMAL/PLANT STUDIES: A prolonged period of hypoglycemia causes irreversible damage to the brain as evidenced in experimental animals by histological changes in the cortex, basal ganglia and rostral parts of the medulla.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

自发低血糖发作...在一位68岁的女性糖尿病患者中报告，该病人在接受胰岛素（每天48单位）治疗的同时，口服了美巴嗪（每天15-25毫克），一种肼类单胺氧化酶抑制剂。

SPONTANEOUS HYPOGLYCEMIC EPISODES...REPORTED IN 68-YR-OLD FEMALE DIABETIC PT RECEIVING INSULIN (48 UNITS/DAY) DURING TREATMENT WITH MEBAMAZINE (15-25 MG/DAY BY MOUTH), A HYDRAZINE MONOAMINE OXIDASE INHIBITOR.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

如果必须同时给予胰岛素和心得安，应定期测定血糖水平以调整（可能减少）胰岛素剂量，如果需要的话。

IF INSULIN & PROPRANOLOL MUST BE GIVEN CONCURRENTLY, PERIODIC SERUM GLUCOSE LEVELS SHOULD BE DETERMINED TO ADJUST (PROBABLY REDUCE) INSULIN DOSAGE IF NECESSARY.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

两名使用胰岛素治疗的病人，在摄入相当于70毫升100度威士忌的35毫升纯酒精后，经历了严重的低血糖发作。

TWO...PATIENTS TREATED WITH INSULIN EXPERIENCED SEVERE HYPOGLYCEMIC EPISODES AFTER INGESTION OF...ALCOHOL /35 ML OF 100% ALCOHOL, EQUAL TO 70 ML 100-PROOF WHISKEY/.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

胰岛素的降血糖作用可能被增强，原因是...同化类固醇、环磷酰胺、单胺氧化酶抑制剂、胍乙啶，或者每日剂量为1.5至6克的 salicylates（水杨酸盐）...在服用利尿剂的病人中，胰岛素的需求可能会增加、减少或保持不变。

HYPOGLCEMIC ACTION OF INSULIN MAY BE POTENTIATED BY...ANABOLIC STEROIDS, CYCLOPHOSPHAMIDE, MONOAMINE OXIDASE INHIBITORS, GUANETHIDINE, OR BY DAILY DOSES OF 1.5 TO 6 G OF SALICYLATES...INSULIN REQUIREMENTS MAY BE INCREASED, DECREASED, OR UNCHANGED IN PATIENTS RECEIVING DIURETICS

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

血浆中外源性胰岛素的一部分可能与某些蛋白质有关，主要是α-和β-球蛋白。这些关联对胰岛素的运输很重要，胰岛素似乎在血液和淋巴中循环。胰岛素的分布体积接近细胞外液的体积。

FRACTION OF...EXOGENOUS INSULIN IN PLASMA MAY BE ASSOC WITH CERTAIN PROTEINS, CHIEFLY ALPHA- & BETA-GLOBULINS. ...THESE ASSOC ARE OF IMPORTANCE FOR TRANSPORT OF INSULIN...WHICH APPEARS TO CIRCULATE IN BLOOD & LYMPH... VOL OF DISTRIBUTION OF INSULIN APPROXIMATES VOL OF EXTRACELLULAR FLUID.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

当胰岛素可以在尿液中检测到时，肾脏会过滤并重新吸收这种激素，肾脏排泄并不是主要的消除途径。肝脏和肾脏在降解激素方面具有首要重要性，每个器官每天都能摧毁几乎40%的产生的胰岛素（30到50单位）。

WHILE INSULIN CAN BE DETECTED IN URINE, THE KIDNEY FILTERS & REABSORBS THE HORMONE & RENAL EXCRETION IS NOT MAJOR ROUTE OF ELIMINATION. LIVER & KIDNEY ARE OF PRIMARY IMPORTANCE IN DEGRADING HORMONE & EACH IS CAPABLE OF DESTROYING ALMOST 40% OF INSULIN PRODUCED PER DAY (30 TO 50 UNITS).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

严重的肾功能损害似乎比肝病更影响循环胰岛素消失的速率...

SEVERE IMPAIRMENT OF RENAL FUNCTION APPEARS TO AFFECT RATE OF DISAPPEARANCE OF CIRCULATING INSULIN TO GREATER EXTENT THAN DOES HEPATIC DISEASE...

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在没有胰岛素的情况下，葡萄糖通过某些细胞膜的传输速率明显降低。

IN ABSENCE OF INSULIN THERE IS MARKED REDUCTION IN RATE OF TRANSPORT OF GLUCOSE ACROSS CERTAIN CELL MEMBRANES.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

序列免疫反应性胰岛素浓度在运动后比休息时高得多。胰岛素从皮下组织的增强吸收可能是通过注射肢体血流量增加来实现的。

SERIAL IMMUNOREACTIVE INSULIN CONCN WERE MUCH HIGHER AFTER EXERCISE THAN THOSE ASSOC WITH REST. THE ENHANCED ABSORPTION OF INSULIN FROM SC TISSUE IS PROBABLY THROUGH AN INCR IN BLOOD FLOW IN INJECTED LIMB.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 安全说明：
  S22,S24/25
• WGK Germany：
  3

制备方法与用途

以上介绍了两种从猪胰腺中提取和纯化胰岛素的方法。它们分别被称为分级提取直接锌盐沉淀法（方法二）以及分级提取间接锌盐沉淀法（方法一）。以下是两者的对比：

1. 方法一主要优点：

   • 提取过程较为简单，无需复杂的设备。
   • 使用硅藻土板框压滤处理，使得过滤效果较好。

2. 方法二主要优点：

   • 通过分级提取提高了纯度和收率。
   • 利用丙酮沉析去除杂质，进一步提高了胰岛素的纯度。

两种方法均涉及以下步骤：

• 提取：使用乙醇和酸（盐酸）从猪胰腺中提取胰岛素；
• 碱化处理与沉淀：通过氨水调节pH值，再加入锌盐促使胰岛素沉淀；
• 脱脂、分级沉析及结晶：除去脂肪等杂质，并进行多次沉析以获得更纯净的产品。

值得注意的是，这两种方法都是在20世纪50年代至60年代初开发出来的技术，在现代生物技术进步的基础上已经逐渐被更加高效和安全的胰岛素生产技术所替代。当前主要采用基因工程方法大规模生产重组人胰岛素。