6-[2-[[(6aR,6bS,8aS,11S,14bS)-11-carboxy-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-2,3,4a,5,6,7,8,9,10,12,12a,14a-dodecahydro-1H-picen-3-yl]oxy]-6-carboxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid | 1405-86-3

• 物质功能分类: 原料药 - 消化系统用药 - 肝病用药
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: 6-[2-[[(6aR,6bS,8aS,11S,14bS)-11-carboxy-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-2,3,4a,5,6,7,8,9,10,12,12a,14a-dodecahydro-1H-picen-3-yl]oxy]-6-carboxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid
• CAS: 1405-86-3
• 化学式: C₄₂H₆₂O₁₆
• 分子量: 822.9
• InChiKey: LPLVUJXQOOQHMX-LUMWQMBZSA-N

物化性质

• 熔点：
  220°C (rough estimate)
• 沸点：
  681.01°C (rough estimate)
• 比旋光度：
  D17 +46.2° (c = 1.5 in alc)
• 密度：
  1.1442 (rough estimate)
• 溶解度：
  DMSO（少量）、乙醇（少量）、甲醇（少量）、吡啶（少量）
• LogP：
  4.64
• 颜色/状态：
  Crystals from glacial acetic acid
• 味道：
  Intensely sweet taste
• 旋光度：
  Specific optical rotation: +46.2 deg @ 17 °C/D (alcohol, 1.5%)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  58
• 可旋转键数：
  7
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  267
• 氢给体数：
  8
• 氢受体数：
  16

ADMET

代谢

给予大鼠门静脉注射甘草酸 bolus，导致血液中一种物质的水平升高，这种物质似乎是甘草次酸作为代谢物形成的葡萄糖醛酸结合物。

BOLUS INJECTION OF GLYCYRRHIZIN GIVEN RATS IN PORTAL VEIN, GAVE RISE IN BLOOD LEVEL OF SUBSTANCE WHICH APPEARS TO BE GLUCURONIC ACID CONJUGATE FORMED AS METABOLITE OF GLYCYRRHETINIC ACID.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在存在10-8 M醛固酮的情况下，添加10-6 M甘草酸显著刺激短路，与仅用醛固酮处理的对照组皮肤相比。

ADDITION OF 10-6 M GLYCYRRHETINIC ACID IN PRESENCE OF 10-8 M ALDOSTERONE STIMULATED SHORT-CIRCUIT SIGNIFICANTLY AS COMPARED WITH CONTROL SKIN TREATED WITH ALDOSTERONE ALONE.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

甘草甜素对皮质类固醇的副作用及增强免疫抑制作用的实验研究。

ADMIN OF GLYCYRRHIZIN DEPRESSED EFFECT OF INJECTED CORTISONE ON GLYCOGEN STORAGE AND ENHANCED IMMUNOSUPPRESSIVE ACTION OF CORTISONE.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

研究了六名健康男性在口服甘草酸（GL）预处理或不预处理的情况下，总泼尼松龙（PSL）和游离泼尼松龙的药代动力学，以确认口服甘草酸是否影响人体内泼尼松龙的代谢。每位受试者静脉注射0.096 mg/kg的泼尼松龙半琥珀酸（PSL-HS），并在之前口服甘草酸50毫克四次。在开始泼尼松龙-HS输注后5、10、15、30、45分钟及1、1.5、2、3、4、6、8、10、12和24小时从外周静脉取血样。通过高效液相色谱法分析血浆中总泼尼松龙的浓度，游离泼尼松龙则通过等渗平衡透析法测量。泼尼松龙的药代动力学参数通过非房室分析确定。研究发现，口服甘草酸显著增加了泼尼松龙半琥珀酸输注后6、8小时的总泼尼松龙浓度，以及4、6和8小时的游离泼尼松龙浓度。此外，口服甘草酸还改变了总泼尼松龙和游离泼尼松龙的药代动力学。口服甘草酸后，药时曲线下面积（AUC）显著增加，总血浆清除率（CL）显著降低，平均滞留时间（MRT）显著延长。然而，分布容积（Vdss）没有明显变化。这表明口服甘草酸通过抑制其代谢而不是影响其分布，增加了血浆泼尼松龙浓度并影响了其药代动力学。

The pharmacokinetics of total and free prednisolone (PSL) in six healthy men, with or without pretreatment with oral glycyrrhizin (GL), was investigated to confirm whether oral administration of GL influences the metabolism of prednisolone in man. Each subject received an intravenous administration of 0.096 mg/kg of prednisolone hemisuccinate (PSL-HS) with or without pretreatment with 50 mg of oral glycyrrhizin four times. Blood samples were taken from a peripheral vein at 5, 10, 15, 30, 45 min and 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hr after the start of prednisolone-HS infusion. The concentrations of total prednisolone in plasma were analyzed by high-performance liquid chromatography, and the free prednisolone was measured by an isocolloidosmolar equilibrium dialysis method. The pharmacokinetic parameters of prednisolone were determined by non-compartment analysis. Oral administration of glycyrrhizin was found to significantly increase the concentrations of total prednisolone at 6, 8 hr, and of free prednisolone at 4, 6 and 8 hr after prednisolone-hemisuccinate infusion. Moreover, oral administration of glycyrrhizin was also found to modify the pharmacokinetics of both total and free prednisolone. After oral administration of glycyrrhizin, the area under the curve (AUC) was significantly increased, the total plasma clearance (CL) was significantly decreased, and the mean residence time (MRT) was significantly prolonged. However, the volume of distribution (Vdss) showed no evident change. This suggests that oral administration of glycyrrhizin increases the plasma prednisolone concentrations and influences its pharmacokinetics by inhibiting its metabolism, but not by affecting its distribution.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

为了澄清甘草酸（甘草根的水提取物，用于治疗慢性活动性肝炎的药物）是否预防四氯化碳、丙烯甲酯和内毒素诱导的肝脏损伤的发展，本研究在大鼠中进行。在四氯化碳给药前20小时给予甘草酸治疗，可以防止中央周围肝细胞坏死的形成。在丙烯甲酯给药前2小时给予甘草酸治疗，也抑制了门周围肝细胞坏死的形成。然而，甘草酸并未预防内毒素诱导的局灶性和随机性肝细胞坏死的形成。这些实验结果表明，甘草酸对内毒素引起的窦状循环障碍后的肝脏损伤没有保护作用，并且甘草酸可以保护由肝毒素（如四氯化碳和丙烯甲酯）对肝细胞的直接作用引起的肝毒性。

To clarify whether glycyrrhizin, the aqueous extract of licorice root and a drug for treatment of chronic active hepatitis, prevents the development of hepatic injury induced by carbon tetrachloride, allyl formate, and endotoxin, the present study was undertaken in rats. The treatment with glycyrrhizin 20 hr before carbon tetrachloride administration protected the development of the pericentral hepatocellular necrosis. Glycyrrhizin treatment 2 hr prior to the administration of allyl formate also inhibited the development of the periportal hepatocellular necrosis. However, glycyrrhizin did not protect the development of endotoxin-induced focal and random hepatocellular necrosis. These experimental results suggest that glycyrrhizin has no protective effect on hepatic injury following sinusoidal circulatory disturbance as seen in the case of endotoxin and that glycyrrhizin can protect against hepatotoxicity induced by the direct action on the hepatocytes due to hepatotoxins, such as carbon tetrachloride and allyl formate.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

为了研究Potenlini对肝硬变动物模型肝脏核因子-κB（NF-κB）结合活性的影响，并阐述Potenlini生物活性的分子机制。方法：雄性SD大鼠随机分为正常对照组、模型对照组和Potenlini组。后两组大鼠用CCl4和乙醇溶液处理以诱导慢性肝损伤。Potenlini组大鼠同时给予Potenlini治疗。所有大鼠在CCl4给药后第9周处死。收集血清和肝脏标本，评估血清ALT活性和组织学发现。制备肝脏组织的核提取物，并进行凝胶阻滞分析以评估NF-κB活性。结果：（1）与模型对照组相比，Potenlini治疗的大鼠血清ALT水平显著降低，模型对照组大鼠ALT水平显著升高。（2）组织学上，模型组大鼠肝脂肪变性和纤维化严重，但Potenlini组大鼠显著改善。（3）与正常肝脏相比，模型对照组大鼠肝脏标本中NF-κB结合活性显著增加，但在Potenlini组大鼠肝脏中结合水平几乎正常。结论：Potenlini可以抑制CCl4和乙醇诱导的慢性肝损伤中的NF-κB结合活性，这可能是Potenlini保护肝脏免受肝毒素诱导的肝损伤和肝硬化的部分机制。

To investigate the effects of Potenlini on nuclear factor-kappa B (NF-kappa B) binding activity in the livers of animals models with liver cirrhosis, and to delineate the molecular mechanism of the bioactivities of Potenlini. METHODS: Male SD rats were randomly allocated into a normal control group, a model control group, and a Potenlini group. Rats in the latter two groups were treated with CCl4 and Ethanol solution in order to induce chronic liver injury. Rats in Potenlini group were given Potenlini treatment at the same time. All rats were killed at the 9th week after CCl4 administration. Serum and liver specimens were collected, serum ALT activities and histological findings were assessed. Nuclear extracts from liver tissues were prepared and gel retardation assays were performed for the evaluation of NF-kappa B activity. RESULTS: (1) Serum ALT levels were significantly reduced in rats treated with Potenlini compared with those in rats of the model control group, which had dramatically increased ALT levels. (2) Histologically, liver steatosis and fibrosis were severe in the rats of the model group, but were significantly improved in rats of the Potenlini group. (3) NF-kappa B binding activity was markedly increased in the liver specimens taken from the rats of the model control group in comparison with the binding of normal livers, but the binding levels were nearly normal in the livers of the Potenlini group. CONCLUSION: Potenlini can inhibit the NF-kappa B binding activity in CCl4 and ethanol induced chronic liver injury, and that may partially be the mechanism by which Potenlini protects liver from hepatotoxin-induced liver injury and cirrhosis.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

甘草酸在大鼠小肠中被吸收；在将甘草酸通过门静脉一次性注射后，血液中检测不到甘草酸；在口服给药后，血液中存在可检测到的甘草酸。

GLYCYRRHIZIN WAS ABSORBED IN RAT SMALL INTESTINE; THERE WAS NO DETECTABLE AMT OF GLYCYRRHETINIC ACID IN BLOOD AFTER BOLUS INJECTION OF GLYCYRRHIZIN INTO PORTAL VEIN; GLYCYRRHETINIC ACID WAS PRESENT IN DETECTABLE AMT IN BLOOD AFTER ORAL ADMIN.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

甘草酸（GZA）和甘草次酸（GRA）可以通过高效液相色谱（HPLC）在实验动物和人类的生物液体和组织中快速准确地测定。从血浆和组织中，甘草酸和甘草次酸可以通过有机溶剂提取，并且提取液可以直接用于HPLC。从胆汁或尿液中提取和测定甘草酸和甘草次酸更加困难，因为存在干扰的内源性化合物以及甘草次酸与葡萄糖醛酸或硫酸盐的结合。可以通过离子对结合后用有机溶剂提取或固相萃取从尿液或胆汁中提取甘草酸和甘草次酸。甘草次酸结合物可以通过色谱分离或用beta-葡萄糖醛酸酶预处理来测定。甘草酸和甘草次酸的药代动力学可以通过中央室的双相消除来描述，具有剂量依赖性的第二消除相。根据剂量不同，甘草酸在人体中的第二消除相的半衰期为3.5小时，而甘草次酸的半衰期在10-30小时之间。甘草酸和甘草次酸的大部分通过胆汁排出。虽然甘草酸可以未经代谢就排出并经历肠肝循环，但甘草次酸在胆汁排泄前会与葡萄糖醛酸或硫酸结合。口服给药的甘草酸几乎完全被肠道细菌水解，并作为甘草次酸进入系统循环。

Glycyrrhizic acid (GZA) and glycyrrhetinic acid (GRA) can be determined rapidly and precisely by high-performance liquid chromatography (HPLC) in biological fluids and tissues from experimental animals and humans. From plasma and tissues, glycyrrhizic acid and glycyrrhetinic acid are extracted by organic solvents and the extracts can directly be used for HPLC. From bile or urine, extraction and determination of glycyrrhizic acid and glycyrrhetinic acid are more difficult due to interfering endogenous compounds and conjugation of glycyrrhetinic acid with glucuronides or sulfates. Extraction of glycyrrhizic acid and glycyrrhetinic acid from urine or bile can be performed by ion-pairing followed by extraction with organic solvents or by solid phase extraction. Glycyrrhetinic acid conjugates can be determined by chromatographic separation or by pretreatment with beta-glucuronidase. The pharmacokinetics of glycyrrhetinic acid and glycyrrhizic acid can be described by a biphasic elimination from the central compartment with a dose-dependent second elimination phase. Depending on the dose, the second elimination phase in humans has a half-life of 3.5 hours for glycyrrhizic acid and between 10-30 hours for glycyrrhetinic acid. The major part of both glycyrrhetinic acid or glycyrrhizic acid is eliminated by the bile. While glycyrrhizic acid can be eliminated unmetabolized and undergoes enterohepatic cycling, Glycyrrhetinic acid is conjugated to glycyrrhetinic acid glucuronide or sulfate prior to biliary excretion. Orally administered glycyrrhizic acid is almost completely hydrolyzed by intestinal bacteria and reaches the systemic circulation as glycyrrhetinic acid.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

甘草酸目前因治疗慢性肝炎而受到临床关注。它也被用作食品产品和咀嚼烟中的甜味剂。在人口中的一些高度暴露的亚群中，已经报告了严重的不良反应，如高血压和电解质紊乱。为了分析暴露于这种化合物的健康风险，定量评估了甘草酸及其活性代谢物的动力学。甘草酸及其代谢物经历复杂的动力学过程，包括肠肝循环和系统前代谢。在人类中，这些过程的详细信息通常难以获得。因此，开发了一个模型，描述了大鼠体内甘草酸及其活性代谢物甘草酸的系统性和胃肠道动力学。由于模型的生理基础结构，可以将早期体外和体内研究的数据直接纳入，包括吸收、肠肝循环和系统前代谢。该模型表明，甘草酸及其代谢物从血浆到胆汁的传输效率很高，可能是通过肝转移蛋白3-α-羟基类固醇脱氢酶。胆汁排泄的代谢物在甘草酸重吸收后的细菌水解导致观察到的甘草酸终末血浆清除延迟。这些基于生理的药代动力学建模分析实验数据得出的机制性发现，最终可用于对含有甘草酸的人类暴露进行定量健康风险评估。版权2000 Academic Press。

Glycyrrhizic acid is currently of clinical interest for treatment of chronic hepatitis. It is also applied as a sweetener in food products and chewing tobacco. In some highly exposed subgroups of the population, serious side effects such as hypertension and electrolyte disturbances have been reported. In order to analyze the health risks of exposure to this compound, the kinetics of glycyrrhizic acid and its active metabolites were evaluated quantitatively. Glycyrrhizic acid and its metabolites are subject to complex kinetic processes, including enterohepatic cycling and presystemic metabolism. In humans, detailed information on these processes is often difficult to obtain. Therefore, a model was developed that describes the systemic and gastrointestinal tract kinetics of glycyrrhizic acid and its active metabolite glycyrrhetic acid in rats. Due to the physiologically based structure of the model, data from earlier in vitro and in vivo studies on absorption, enterohepatic cycling, and presystemic metabolism could be incorporated directly. The model demonstrates that glycyrrhizic acid and metabolites are transported efficiently from plasma to the bile, possibly by the hepatic transfer protein 3-alpha-hydroxysteroid dehydrogenase. Bacterial hydrolysis of the biliary excreted metabolites following reuptake of glycyrrhetic acid causes the observed delay in the terminal plasma clearance of glycyrrhetic acid. These mechanistic findings, derived from analysis of experimental data through physiologically based pharmacokinetic modeling, can eventually be used for a quantitative health risk assessment of human exposure to glycyrrhizic acid containing products. Copyright 2000 Academic Press.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

为了评估异生物质结合物胆汁排泄的多重性，研究了在大鼠静脉注射10 mg/kg甘草酸和静脉输注抑制剂溴磺酚酞和靛青绿后甘草酸的胆汁排泄情况。靛青绿并未影响甘草酸的胆汁排泄，而溴磺酚酞则显著减少了它的排泄。甘草酸的血浆水平因溴磺酚酞而增加，但靛青绿则没有影响。在Eisai高胆红素血症大鼠中，甘草酸的胆汁排泄严重受损，导致血浆水平升高。这些发现表明，甘草酸的胆汁排泄是由 liquiritigenin 葡糖苷酸和溴磺酚酞共享的系统介导的，而不是由靛青绿介导的，并且这个系统在Eisai高胆红素血症大鼠中是遗传性缺陷的。

To assess the multiplicity for the biliary excretion of xenobiotic conjugates, glycyrrhizic acid (glycyrrhizin) was studied in rats after intravenous (IV) injection of 10 mg/kg glycyrrhizic acid and IV infusion of inhibitors, dibromosulfophthalein and indocyanine green. Indocyanine green did not affect the biliary excretion of glycyrrhizic acid, whereas dibromosulfophthalein reduced it significantly. The plasma level of glycyrrhizic acid was increased by dibromosulfophthalein, but not by indocyanine green. In Eisai hyperbilirubinemic rats, the biliary excretion of glycyrrhizic acid was severely impaired, resulting in an increased plasma level. The findings suggested that the biliary excretion of glycyrrhizic acid is mediated by the system shared by liquiritigenin glucuronides and dibromosulfophthalein, but not by indocyanine green, and that the system is hereditarily defective in Eisai hyperbilirubinemic rats.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 安全说明：
  S22,S24/25
• WGK Germany：
  3
• 海关编码：
  1211903600
• 危险品运输编号：
  NONH for all modes of transport
• RTECS号：
  MD2025000

制备方法与用途

以下是关于甘草酸的生产方法、用途及特点：

生产方法

1. 由甘草提取：首先将甘草根茎干燥并粉碎成粉末（保留纤维部分），取200kg粉末及纤维，加水1200kg，在85-100℃下浸提2小时。过滤后滤渣再用1000kg水提取2小时，过滤后再重复浸提一次。合并三次滤液，在搪瓷蒸发器中浓缩至原体积的1/5。

2. 加入乙醇：冷却后的滤液加入95%乙醇使乙醇浓度达65%，静置24小时后过滤，除去植物蛋白和多糖等杂质。

3. pH调节与沉淀：将滤液调至pH值为3，甘草酸析出沉淀。过滤洗涤后，加入3倍体积的丙酮，加热回流3小时，倾倒丙酮提取液。残渣再反复回流提取两次，合并三次提取液，过滤回收丙酮。

4. 干燥与粉碎：滤干的湿甘草酸在45℃下干燥1小时，然后缓缓升温至85-95℃，快烘干时升至100-105℃烘5分钟。最终经粉碎后即得成品。

用途

1. 食品工业：

   • 可作为调味料和甜味剂添加于饼干、肉禽罐头、调味料、糖果、蜜饯、凉果和饮料中。
   • 在酱油中用于改善咸味，提高固有味道并消除糖精的苦味。在腌制咸菜卤水中可消除糖精的苦味，在腌制过程中防止因少加糖而引起的发酵败坏、变色及硬化等问题。
   • 增加豆酱甜味，使味道均匀。

2. 医疗与保健：

   • 具有抗炎、抗变态反应作用；肾上腺皮质激素样效果如抑制毛细血管通透性，减轻过敏性休克症状等。
   • 降低高血压患者的血清胆固醇水平，并可作为抗癌防癌药物使用。具有类似糖皮质激素的药理作用但无严重不良反应。

3. 其他用途：

   • 可用作食品添加剂如豆酱、酱油中的甜味剂。

特点

• 甘草酸是从天然植物甘草中提取的主要活性成分，具有较强的甜度（约为砂糖的250倍）。
• 作为药物时可用于治疗各种急慢性肝炎、支气管炎及艾滋病等。
• 在临床应用中，甘草酸因其类似肾上腺皮质激素的作用而被广泛应用。

文献信息

• Glycyrrhizin or derivatives thereof for for treating or preventing severe acute respiratory syndrome (sars)
  申请人：Cinatl Jindrich

  公开号：US20070099855A1

  公开（公告）日：2007-05-03

  The invention provides methods for preventing, treating, managing or ameliorating viral infections, in particular, Severe Acute Respiratory Syndrome (SARS). More specifically, the invention provides methods for preventing, treating, managing or ameliorating a SARS-associated coronavirus or one or more symptoms thereof by administering Glycyrrhizin and/or derivatives thereof The invention also provides methods for preventing, treating, managing or ameliorating a SARS-associated coronavirus or one or more symptoms thereof by administering Glycyrrhizin and/or a derivative thereof in combination with a prophylactic or therapeutic agent other than Glycyrrhizin or a derivative thereof.