地黄苷元 | 1672-46-4

• 物质功能分类: 分析化学 - 标准品 - 法医和兽医标准品
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 中文名称: 地黄苷元
• 中文别名: 异羟黄毒苷
• 英文名称: digoxigenin
• 英文别名: 3-[(3S,5R,8R,9S,10S,12R,13S,14S,17R)-3,12,14-trihydroxy-10,13-dimethyl-1,2,3,4,5,6,7,8,9,11,12,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]-2H-furan-5-one
• CAS: 1672-46-4
• 化学式: C₂₃H₃₄O₅
• mdl: MFCD00871861
• 分子量: 390.52
• InChiKey: SHIBSTMRCDJXLN-KCZCNTNESA-N

物化性质

• 熔点：
  222 °C(lit.)
• 沸点：
  435.71°C (rough estimate)
• 密度：
  1.0639 (rough estimate)
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）
• 颜色/状态：
  Prisms from ethyl acetate
• 蒸汽压力：
  8.41X10-15 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Stable under recommended storage conditions.
• 分解：
  When heated to decomposition it emits acrid smoke and fumes.
• 碰撞截面：
  195.1 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  28
• 可旋转键数：
  1
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.869
• 拓扑面积：
  87
• 氢给体数：
  3
• 氢受体数：
  5

ADMET

代谢

体外代谢地高辛及其裂解相关化合物使用原代培养的肝细胞和从人肝脏中分离的微粒体部分进行了研究。在这些模型上，地高辛（DG3）和地高辛双糖苷（DG2）在体外并未显著代谢……因此，DG3和DG2糖的逐步裂解似乎不依赖于细胞色素P450。这个酶系统在人类中对于这一特定反应可能只发挥很小的作用。然而，已知在DG3胃内水解后形成的地高辛单糖苷（DG1）和地高辛（DG0）被广泛转化为极性化合物（主要是葡萄糖苷酸）。此外，使用人肝微粒体，展示了负责DG1葡萄糖苷酸化的UDP-葡萄糖苷酸转移酶（UDPGT）活性存在广泛的变异性。这些结果表明，两个主要因素可能有助于地高辛生物转化的个体间总体变异性：1）个体的胃内pH，影响导致DG1和DG0的糖裂解；2）对洋地黄化合物结合特异的肝UDPGT水平存在变异性。

In vitro metabolism of digoxin and its cleavage-related compounds was investigated using hepatocytes in primary culture and microsomal fractions both isolated from human livers. On these models, digoxin (DG3) and digoxigenin bisdigitoxoside (DG2) were not shown to be significantly metabolized in vitro ... Therefore, it appeared that the stepwise cleavage of DG3 and DG2 sugars was not cytochrome P450 dependent. This enzymatic system probably plays a minor role in humans for this particular reaction. However, digoxigenin monodigitoxoside (DG1) and digoxigenin (DG0) which are known to be formed after intra-gastric hydrolysis of DG3, were extensively converted to polar compounds (mainly glucuronides). In addition, using human liver microsomes, a wide variability in UDP-glucuronyl transferase (UDPGT) activities responsible for DG1 glucuronidation was demonstrated. These results suggest that two main factors may contribute to the overall interindividual variability of digoxin biotransformation: 1), the individual intra-gastric pH which influences the sugar cleavage leading to DG1 and DG0; ii), a variability in the level of the hepatic UDPGT specific for digitalis compounds conjugation.

来源:Hazardous Substances Data Bank (HSDB)

代谢

地高辛（I）的生物转化在2名健康男性摄入标记（7.5微克）和非标记（3毫克）I后进行了研究。在30分钟时血清中的放射性，<26%与I一起色谱分离；其余的作为代谢物色谱分离，其中大多数是极性的。鉴定出的主要极性代谢物是3-表地高辛的葡萄糖苷酸。代谢物与地高辛抗血清之间存在广泛的交叉反应。

Digoxigenin (I) biotransformation was investigated in 2 healthy men following ingestion of labeled (7.5 ug) and unlabeled (3 mg) I. Of the radioactivity in serum at 30 min, <26% chromatographed with I; the rest chromatographed as metabolites, most of which were polar. The main polar metabolites identified were glucuronides of 3-epidigoxigenin. There was extensive cross reactivity between metabolites and antisera to digoxin.

来源:Hazardous Substances Data Bank (HSDB)

代谢

地高辛（Dg3）依次转化为双地高辛苷（Dg2）、单地高辛苷（Dg1）和地高辛苷元（Dg0）在大鼠肝微粒体的代谢过程进行了研究。动力学研究的结果与单一酶机制描述的连续氧化断裂一致。形成Dg2的平均（+/-SD）Km和Vmax分别为125 +/- 22 uM和362 +/- 37 pmol/min/mg蛋白。形成Dg1的相应值分别为61 +/- 5微M和7 +/-1 pmol/min/mg蛋白。Dg0形成的表观值为30 +/- 9 uM和310 +/- 30 pmol/min/mg蛋白。细胞色素P450（CYP）3A亚家族的化学抑制，如酮康唑和三乙酰奥兰多霉素，可减少Dg2和Dg1的形成，最多可达90%。针对大鼠CYP3A2的特异性抗体，可降低Dg3和Dg2的氧化断裂速率，最多可达85%。通过化学和免疫抑制CYP2E1、CYP2C亚家族和CYP1A2，并未影响Dg3和Dg2的初始代谢速率。相反，Dg1的代谢不受三乙酰奥兰多霉素以及针对CYP3A2、CYP2C11、CYP2E1、CYP2B1/2B2和CYP1A2的抗体的 影响。然而，它被格司特德和17α-炔雌醇（选择性抑制人CYP3A）抑制了超过80%。总的来说，这些数据支持了CYP3A在大鼠肝微粒体中断裂Dg3和Dg2的作用。尚未确定代谢Dg1的酶。

The sequential metabolism of digoxin (Dg3) to digoxigenin bis-digitoxoside (Dg2), digoxigenin mono-digitoxoside (Dg1) and digoxigenin (Dg0) was investigated in rat liver microsomes. Kinetic studies produced results consistent with a single enzyme mechanism describing the successive oxidative cleavages. Formation of Dg2 was catalysed with mean (+/-SD) Km and Vmax of 125 +/- 22 uM and 362 +/- 37 pmol/min/mg protein, respectively. The corresponding values for the formation of Dg1 were 61 +/- 5 microM and 7 +/-1 pmol/min/mg protein. Dg0 formation was catalysed with the apparent values of 30 +/- 9 uM and 310 +/- 30 pmol/min/mg protein. Chemical inhibition of cytochrome P450 (CYP) 3A subfamily with ketoconazole and triacetyoleandomycin decreased the formation of Dg2 and Dg1 by up to 90%. Antibodies specific to rat CYP3A2 lowered the rate of oxidative cleavage of Dg3 and Dg2 by up to 85%. Inhibition of CYP2E1, CYP2C subfamily and CYP1A2 by chemical and immuno-inhibition did not affect initial rates of metabolism of Dg3 and Dg2. In contrast, Dg1 metab was not affected by triacetyloleandomycin as well as by antibodies to CYP3A2, CYP2C11, CYP2E1, CYP2B1/2B2 and CYP1A2. It was however inhibited by >80% by gestodene and 17alpha-ethynylestradiol (selective inhibitors of human CYP3A). Collectively, these data support the involvement of CYP3A in the cleavage of Dg3 and Dg2 in rat liver microsomes. The enzyme-metabolizing Dg1 remains to be identified.

来源:Hazardous Substances Data Bank (HSDB)

代谢

人类肝脏乙醇脱氢酶（乙醇：NAD氧化还原酶，EC 1.1.1.1）催化了洋地黄毒苷、地高辛苷和吉妥辛苷的3位β-羟基团氧化成它们的3-酮衍生物。人类肝脏乙醇脱氢酶是一种依赖于NAD(H)的肝脏酶，特异性地作用于心脏苷元C3位的自由羟基团；这个羟基是苷元在人体内酶促氧化和伴随的药理学失活的关键位点。几种动力学方法已经证明，乙醇和药理活性的洋地黄糖苷成分在人类肝脏乙醇脱氢酶的同一位点以非常相似的kcat/Km值被氧化，它们在此位点上相互竞争。因此，人类肝脏乙醇脱氢酶成为乙醇和这些糖苷在代谢、药理学和毒理学中的重要的生化链接，尽管这些结构不相关的物质都被广泛使用。

Human liver alcohol dehydrogenase (alcohol: NAD" oxidoreductase, EC 1.1.1.1) catalyzes the oxidation of the 3 beta-OH group of digitoxigenin, digoxigenin, and gitoxigenin to their 3-keto derivatives. Human liver alcohol dehydrogenase is the NAD(H)-dependent liver enzyme specific for the free hydroxyl group at C3 of the cardiac genins; this hydroxyl is the critical site of the genins' enzymatic oxidation and concomitant pharmacological inactivation in humans. Several kinetic approaches have demonstrated that ethanol and the pharmacologically active components of the digitalis glycosides are oxidized with closely similar kcat/Km values at the same site on human liver alcohol dehydrogenase, for which they compete. Human liver alcohol dehydrogenase thereby becomes an important biochemical link in the metabolism, pharmacology, and toxicology of ethanol and these glycosides, structurally unrelated agents that are both used widely.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

洋地黄毒苷是洋地黄的一种代谢物，可以通过洋地黄的水解产生。人类研究：所有心脏糖苷类及其苷元对培养的人类和猴子细胞相比小鼠、叙利亚仓鼠和中国仓鼠来源的细胞系展现出了超过100倍的高毒性。动物研究：研究了细胞内可用的Na+离子对Na+, K+-腺苷三磷酸酶影响洋地黄毒苷的作用，从而引起钠泵抑制和正性肌力作用的可能。这一作用在用电刺激的豚鼠心脏隔离的左心房中进行了检查。当心房以3 Hz的频率刺激时，洋地黄毒苷的正性肌力作用发展得比1.5 Hz时更快。正性肌力作用发展速率取决于膜去极化的频率，而不是收缩。在静息心房中，洋地黄毒苷以浓度依赖性方式抑制了钠泵活性，如通过对哇巴因敏感的86Rb摄取所估计。电刺激增强了这种抑制，使浓度-抑制曲线向左移动。膜去极化也影响了钠泵对洋地黄毒苷的敏感性，这表明细胞内Na+的作用。这些数据表明，与心脏糖苷类似，苷元与Na+,K+-腺苷三磷酸酶的相互作用对于这种物质的正性肌力作用的发挥是必不可少的。

IDENTIFICATION AND USE: Digoxigenin is a metabolite of digoxin and it can be produced by hydrolysis of digoxin. HUMAN STUDIES: All cardiac glycosides and their genins exhibited greater than 100-fold higher toxicity towards cultured human and monkey cells in comparison to the cell lines of mouse, Syrian hamster, and Chinese hamster origins. ANIMAL STUDIES: A possibility that intracellular Na+ ions available to Na+, K+-adenosine triphosphatase influence the action of digoxigenin to cause sodium-pump inhibition and a positive inotropic effect was examined with isolated left atria of guinea-pig hearts. The positive inotropic action of digoxigenin developed more rapidly when atria were stimulated at 3 Hz than at 1.5 Hz. The rate of development of the positive inotropic action was dependent on the frequency of membrane depolarizations rather than on contractions. Sodium pump activity, as estimated from ouabain-sensitive 86Rb uptake, was inhibited by digoxigenin in a concentration-dependent manner in quiescent atria. The inhibition was enhanced by electrical stimulation which shifted the concentration-inhibition curves to the left. The sensitivity of the sodium pump for digoxigenin was also affected by membrane depolarizations, suggesting a role for intracellular Na+. These data indicate that similar to the cardiac glycosides, the interaction of the aglycone with Na+,K+-adenosine triphosphatase is essential for the development of the positive inotropic action of this agent.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

乙醇与心脏固醇的竞争以及洋地黄衍生物治疗使用的安全范围较窄，似乎都增加了那些接受洋地黄治疗并同时大量摄入乙醇，或者其酒精脱氢酶功能受损的个体的风险。

Both the competition of ethanol with cardiac sterols and the narrow margin of safety in the therapeutic use of digitalis derivatives would seem to place at increased risk those individuals who receive digitalis and simultaneously consume large amounts of ethanol or whose alcohol dehydrogenase function is impaired.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

紧急和支持性措施。1. 保持呼吸道通畅，必要时协助通气。2. 由于组织分布延迟，在显著摄入后至少12-24小时内密切监测患者。3. 使用地高辛特异性抗体治疗高钾血症；钙（10%葡萄糖酸钙...碳酸氢钠...和/或聚苯乙烯磺酸钠（Kayexalate ...。a. 注意：尽管广泛建议在地高辛中毒患者中避免使用钙，因为担心它会恶化室性心律失常，但这一警告基于旧的且非常弱的病例报告，并未得到动物研究的证实。钙是治疗高钾血症引起的生命威胁性心脏毒性的首选药物。b. 轻度高钾血症实际上可能预防心动过速。4. 应纠正低钾血症和低镁血症，因为这些可能有助于心脏毒性。5. 使用阿托品治疗心动过缓或心脏传导阻滞...。对于持续的有症状心动过缓，可能需要临时经静脉心脏起搏器，但由于起搏器可能在地高辛中毒患者中引发严重心律失常，因此建议仅在缺乏地高辛特异性抗体或地高辛特异性抗体失效时使用起搏器。6. 室性心动过速可能对纠正低钾或镁有反应。利多卡因和苯妥英钠已被使用，但地高辛特异性抗体是治疗生命威胁性心律失常的首选。避免使用奎尼丁、普鲁卡因胺和其他1a型或1c型抗心律失常药物。/地高辛和其他强心苷/

Emergency and supportive measures. 1. Maintain on open airway and assist ventilation if necessary. 2. Monitor the patient closely for at least 12-24 hours after significant ingestion because of delayed tissue distribution. 3. Treat hyperkalemia with digoxin-specific antibodies; calcium (calcium gluconate 10% ... sodium bicarbonate ... and/or sodium polystyrene sulfonate (Kayexalate ... . a. NOTE: Although it is widely recommended that calcium be avoided inpatients with cardiac glycoside toxicity because of concern that it will worsen ventricular arrhythmias, this warning is based on old and very weak case reports and is not substantiated by animal studies. Calcium is the drug of choice for life-threatening cardiac toxicity due to hyperkalemia. b. Mild hyperkalemia may actually protect against tachyarrhythmias. 4. Hypokalemia and hypomagnesemia should be corrected, as these may contribute to cardiac toxicity. 5. Treat bradycardia or heart block with atropine, ... . temporary transvenous cardiac pacemaker amy be needed for persistent symptomatic bradycardia, but because a pacemaker may trigger serious arrhythmias in patients with digitalis toxicity, pacing is recommended only after failure or unavailability of digoxin-specific antibodies. 6. Ventricular tachyarrhythmias may respond to correction of low potassium or magnesium. Lidocaine and phenytoin have been used, but digoxin-specific antibody is the preferred treatment for life-threatening arrhythmias. Avoid quinidine, procainamide, and other type 1a or 1c antiarrhythmic drugs. /Digoxin and other cardiac glycosides/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

特定的药物和解毒剂。例如，地高辛特异性抗体片段（如DigiFab）在逆转地高辛毒性方面非常有效，适用于严重中毒。这包括高钾血症（>mEq/L），有症状的心律失常，高度房室传导阻滞，室性心律失常和血流动力学不稳定。还应在地高辛中毒且伴有肾衰竭的患者以及大量口服过量和血药浓度高的患者预防性治疗中考虑使用地高辛抗体。地高辛抗体迅速与地高辛结合，在较小程度上与洋地黄和其他心脏糖苷结合。形成的非活性复合物会迅速通过尿液排出。... /地高辛和其他心脏糖苷/

Specific drugs and antidotes. Fab fragments of digoxin-specific antibodies (eg, DigiFab) are highly effective in reversing digoxin toxicity and are indicated for significant poisoning. This includes hyperkalemia (>mEq/L), symptomatic arrhythmias, high degree AV block, ventricular arrhythmias, and hemodynamic instability. Digoxin antibodies should also be considered in digoxin-toxic patients with renal failure and for prophylactic treatment in a patient with massive oral overdose and high serum levels. Digoxin antibodies rapidly bind to digoxin and, to a lesser extent, digitoxin and other cardiac glycoside. The inactive complex that is formed in excreted rapidly in the urine. ... /Digoxin and other cardiac glycosides/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

解毒。如果条件适当，口服活性炭。在小到中等剂量摄入后，如果能及时给予活性炭，则无需进行洗胃。/地高辛和其他强心苷/

Decontamination. Administer activated charcoal orally 9if conditions are appropriate. Gastric lavage is not necessary after small-to-moderate ingestions if activated charcoal can be given promptly. /Digoxin and other cardiac glycosides/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

开发了一种用于精确测定心脏和肾脏尸检样本中的地高辛和洋地黄毒苷，以及它们的半合成衍生物和依赖性心脏活性代谢物的方法。一组长期使用治疗剂量β-乙酰地高辛的6名患者，心肌地高辛含量平均为46.1 +/- 25.0 ng/g（标准差）；肾脏：50.3 +/- 30.3 ng/g。地高辛双洋地黄苷是心脏和肾脏中第二重要的代谢物；其次是地高辛单洋地黄苷和地高辛。在一组维持使用洋地黄毒苷治疗的七名患者中，平均组织水平较高，但代谢模式相似（心肌洋地黄毒苷含量：78.9 +/- 38.4 ng/g，肾含量：104.1 +/- 44.1 ng/g）。长期使用洋地黄毒苷治疗在心脏和肾脏中通过羟基化形成地高辛的量约为10 ng/g。一例地高辛中毒的病例在组织含量和代谢分布上都有所不同。

A method was developed for the specific determination of digoxin and digitoxin, as well as their semisynthetic derivatives and dependent cardioactive metabolites, in autopsy samples of heart and kidney. A collective of 6 patients on long-term treatment with therapeutic doses of beta-acetyldigoxin had a mean myocardial digoxin content of 46.1 +/- 25.0 ng/g (SD); kidney: 50.3 +/- 30.3 ng/g. Digoxigenin bisdigitoxoside represented the second most important metabolite in heart and kidney; digoxigenin monodigitoxoside and digoxigenin follow, respectively. In a collective of seven patients on maintenance treatment with digitoxin, the mean tissue levels were higher but the metabolic pattern was similar (myocardial digitoxin content: 78.9 +/- 38.4 ng/g, renal content: 104.1 +/- 44.1 ng/g). The amount of digoxin formed by hydroxylation under long-term treatment with digitoxin in heart and kidney were approx 10 ng/g. A case of digoxin intoxication differed both in the tissue content and in the metabolic distribution.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(a)
• 危险品标志：
  T+
• 安全说明：
  S36/37/39,S45
• 危险类别码：
  R26/27/28
• WGK Germany：
  3
• 危险品运输编号：
  UN 2811 6.1/PG 1
• RTECS号：
  FH5390000
• 包装等级：
  II
• 危险类别：
  6.1(a)

制备方法与用途

生物活性

Digoxigenin 是一种半抗原，尽管其为小分子，却具有较高的抗原性，广泛应用于多种分子生物学领域。它常被用作替代探针，用于标记原位杂交实验。

反应信息

• 作为反应物：
  描述：

  地黄苷元 在 吡啶 、 chromium(VI) oxide 、 氯化亚砜 、 溶剂黄146 、 铂 作用下， 生成 3β,11β-Diacetoxy-12-oxo-5β,17αH-aetiansaeuremethylester
  参考文献：
  名称：

  合成von3β，12β-Diacetoxy-11-keto-ätiansäure-methyl-ester和zweier异构体Ätiansäureester。Gallensäurenund verwandte Stoffe，49岁。

  摘要：

  地高辛中的地高辛配基在schlechter Ausbeute ua das 12-O-Acetyldigoxigenin（II）中。3,12-二-O-乙酰基洋地黄毒苷（VI）ur 3-β-Acatoxy-12-酮基-天青-甲基酯（VIII）abgebaut，und daraus wurde durch Bromieren 3，β-乙酰氧基-12-酮基11ξ-溴-ätiansäure-甲酯（IX）hergestellt。

  DOI：

  10.1002/hlca.19560390629
• 作为产物：
  描述：

  毛花苷C 在 盐酸 、 乙醇 、 水 作用下， 生成 地黄苷元
  参考文献：
  名称：

  洋地黄苷，洋地黄A，B和C

  摘要：

  DOI：

  10.1002/hlca.193301601136

文献信息

• [EN] COMPOSITIONS AND METHODS COMPRISING SUBSTITUTED 2-AMINOIMIDAZOLES<br/>[FR] COMPOSITIONS ET PROCÉDÉS COMPRENANT DES 2-AMINOIMIDAZOLES SUBSTITUÉS
  申请人：CURZA GLOBAL LLC

  公开号：WO2018184019A1

  公开（公告）日：2018-10-04

  The present invention presents 2-(acylamino)imidazoles with therapeutic activity, including selective activity against cancer cells, and compositions comprising them. Methods of using and preparing the 2-(acylamino)imidazoles are also presented.

  本发明提供了具有治疗活性的2-(酰胺基)咪唑，包括对癌细胞具有选择性活性的化合物，并包括这些化合物的组合物。还提供了使用和制备2-(酰胺基)咪唑的方法。
• [EN] METHODS AND COMPOSITIONS FOR SUBSTANCE USE DISORDER VACCINE FORMULATIONS AND USES THEREOF<br/>[FR] MÉTHODES ET COMPOSITIONS DESTINÉES À DES FORMULATIONS VACCINALES CONTRE DES TROUBLES LIÉS À UNE SUBSTANCE, ET LEURS UTILISATIONS
  申请人：MOLECULAR EXPRESS INC

  公开号：WO2018231706A1

  公开（公告）日：2018-12-20

  The present invention relates to vaccine compositions for treatment of substance use disorders, methods for the manufacture thereof, and methods for the use thereof to treat an animal. These compositions comprise a hapten conjugated via a linker to a protein scaffold and mixed with a particulate carrier and at least one immunostimulatory adjuvant molecule.

  本发明涉及用于治疗物质使用障碍的疫苗组合物，其制造方法以及用于治疗动物的方法。这些组合物包括通过连接剂与蛋白质支架结合的半抗原，并与颗粒载体和至少一种免疫刺激性佐剂分子混合。
• [EN] IMMUNOPHILIN BINDING AGENTS AND USES THEREOF<br/>[FR] AGENTS DE LIAISON À L'IMMUNOPHILINE ET LEURS UTILISATIONS
  申请人：UNIV CALIFORNIA

  公开号：WO2020163594A1

  公开（公告）日：2020-08-13

  Described herein, inter alia, are immunophilin binding compounds and methods of treating CNS diseases, including co-administering outside the CNS of a subject an anti-CNS disease drug and a compound described herein.

  本文描述了免疫蛋白结合化合物以及治疗中枢神经系统疾病的方法，包括在主体的中枢神经系统外联合给予一种抗中枢神经系统疾病药物和本文描述的化合物。
• [EN] HETEROBIFUNCTIONAL ESTERS FOR USE IN LABELING TARGET MOLECULES<br/>[FR] ESTERS HÉTÉROBIFONCTIONNELS À UTILISER DANS MARQUAGE DE MOLÉCULES CIBLES
  申请人：LIFE TECHNOLOGIES CORP

  公开号：WO2012134925A1

  公开（公告）日：2012-10-04

  The present disclosure is directed to a reactive ester agent for conjugating a click-reactive group to a carrier molecule or solid support. The reactive ester agent has the general formula IA, wherein the variables R1, R2, R3, Ra and L are described throughout the application.

  本发明涉及一种用于将点击反应性基团共轭到载体分子或固体支持物上的反应性酯试剂。该反应性酯试剂具有一般公式IA，其中变量R1、R2、R3、Ra和L在申请中有所描述。
• Effects of cyclodextrins on the acid hydrolysis of digoxin
  作者：K UEKAMA、T FUJINAGA、F HIRAYAMA、M OTAGIRI、Y KURONO、K IKEDA

  DOI：10.1111/j.2042-7158.1982.tb04690.x

  日期：2011.4.12

  The effects of three cyclodextrins (α-, β-, γ-CyD) on the acid hydrolysis of digoxin were examined. From the high performance liquid chromatographic tracing of each of the four components (digoxin, bisdigitoxoside, monodigitoxoside, digoxigenin) in reaction mixtures, the individual rate constants (k1-k6) were determined by analogue computer simulation. The hydrolysis was suppressed by CyDs in the order of β-&gt;γ-&gt;α-CyD, where β-CyD inhibited the appearance rates of digoxigenin (k3, k5, and k6) significantly. In the dissolution study of digoxin tablets, the increase in dissolution rate and decrease in acid hydrolysis were attained by inclusion complexation. The data are presented suggesting that CyDs are useful for improving the oral bioavailability of digoxin.

  标题：摘要 研究了三种环糊精（α-，β-，γ-CyD）对洋地黄酸水解的影响。通过对反应混合物中四种成分（洋地黄，双洋地黄苷，单洋地黄苷，洋地黄素）的每个成分的高效液相色谱追踪，通过模拟计算机模拟确定了各自的速率常数（k1-k6）。水解被CyDs抑制的顺序为β->γ->α-CyD，其中β-CyD显著抑制了洋地黄素的出现速率（k3，k5和k6）。在洋地黄片剂的溶解研究中，通过包合络合增加了溶解速率并减少了酸水解。数据显示，CyDs对于提高洋地黄的口服生物利用度是有用的。

表征谱图