(2R,3R,4R,5S,6S)-5-[(2R,3R,4R,5S,6S)-5-[(2R,3R,4S,5S,6S)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6R)-4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-en-1-yl]amino]oxan-2-yl]oxy-3,4-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,4-triol | 56180-94-0

• 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 - 有机氧化合物
• 英文名称: (2R,3R,4R,5S,6S)-5-[(2R,3R,4R,5S,6S)-5-[(2R,3R,4S,5S,6S)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6R)-4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-en-1-yl]amino]oxan-2-yl]oxy-3,4-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,4-triol
• CAS: 56180-94-0
• 化学式: C₂₅H₄₃NO₁₈
• 分子量: 645.6
• InChiKey: XUFXOAAUWZOOIT-PCKYEMPFSA-N

物化性质

• 熔点：
  165-170°C
• 比旋光度：
  D18 +165° (c = 0.4 in water)
• 沸点：
  675.05°C (rough estimate)
• 密度：
  1.4278 (rough estimate)
• 溶解度：
  极易溶于水，溶于甲醇，几乎不溶于二氯甲烷。
• LogP：
  -7.935 (est)
• 颜色/状态：
  Amorphous powder
• 旋光度：
  Specific optical rotation: +165 deg at 18 °C/D (c = 0.4 in water)
• 解离常数：
  pKa = 5.1

计算性质

• 辛醇/水分配系数(LogP)：
  -8.5
• 重原子数：
  44
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.92
• 拓扑面积：
  321
• 氢给体数：
  14
• 氢受体数：
  19

ADMET

代谢

阿卡波糖仅在消化道内代谢，主要由肠道细菌以及消化酶进行。至少已经通过色谱法从尿液中分离出13种代谢物。主要的代谢物被鉴定为4-甲基pyrogallol衍生物（即硫酸盐、甲基和葡萄糖苷酸结合物）。一种代谢物（通过从阿卡波糖上断裂一个葡萄糖分子形成）也具有α-葡萄糖苷酶抑制活性。这种代谢物与从尿液中回收的母化合物一起，占总给药剂量的不到2%。

Acarbose is metabolized exclusively within the gastrointestinal tract, principally by intestinal bacteria, but also by digestive enzymes. ... At least 13 metabolites have been separated chromatographically from urine specimens. The major metabolites have been identified as 4-methylpyrogallol derivatives (i.e., sulfate, methyl, and glucuronide conjugates). One metabolite (formed by cleavage of a glucose molecule from acarbose) also has alpha-glucosidase inhibitory activity. This metabolite, together with the parent compound, recovered from the urine, accounts for less than 2% of the total administered dose.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

在几项大型临床试验中，与安慰剂相比，阿卡波糖治疗（2%至5%）导致血清酶水平升高超过正常上限3倍的情况更为常见，但所有升高均无症状，并在停止治疗后迅速恢复。这些研究报告中没有出现临床明显的肝损伤实例。然而，在获得批准并广泛临床使用后，至少有十几例临床明显的肝损伤与阿卡波糖使用有关。肝损伤通常在开始治疗后的2到8个月内出现，并伴有肝细胞模式的血清酶升高，血清ALT水平显著升高，提示急性病毒性肝炎。免疫过敏特征和自身抗体形成并不典型。虽然大多数病例病情较轻，但有些病例伴有明显黄疸，并有死亡病例报告给申办方。没有将慢性肝损伤或消失胆管综合征与阿卡波糖使用联系起来的案例，大多数药物引起的肝损伤和急性肝衰竭的大型病例系列中也没有识别出由阿卡波糖引起的病例。在几个实例中进行了重新挑战，并导致病程缩短。

In several large clinical trials, serum enzyme elevations above 3 times the upper limit of normal were more common with acarbose therapy (2% to 5%) than with placebo, but all elevations were asymptomatic and resolved rapidly with stopping therapy. These studies reported no instances of clinically apparent liver injury. Subsequent to approval and with wide clinical use, however, at least a dozen instances of clinically apparent liver injury have been linked to acarbose use. The liver injury typically arises 2 to 8 months after starting therapy and is associated with a hepatocellular pattern of serum enzyme elevations with marked increases in serum ALT levels, suggestive of acute viral hepatitis. Immunoallergic features and autoantibody formation are not typical. While most cases are mild, some are associated with marked jaundice and cases with a fatal outcome have been reported to the sponsor. No cases of chronic liver injury or vanishing bile duct syndrome have been linked to acarbose use, and most large series of cases of drug induced liver injury and acute liver failure have not identified cases due to acarbose. Rechallenge has been carried out in several instances and resulted in recurrence with a shortening of the time to onset.

来源:LiverTox

毒理性

• 相互作用

...报告了地高辛和阿卡波糖之间可能存在相互作用。在这些报告中，地高辛的吸收被同时给予阿卡波糖显著减少。阿卡波糖的降糖作用源于对α-葡萄糖苷酶的可逆性和竞争性抑制，该酶水解后来作为葡萄糖分子吸收的寡糖。阿卡波糖仅在小肠中发挥作用，大部分以原形出现在粪便中。地高辛是一种用于治疗心力衰竭和/或慢性房颤的知名药物。阿卡波糖延迟人类对蔗糖和淀粉的消化；因此，随后会出现胃肠道转运障碍，导致稀便。因此，阿卡波糖的联合使用可能会增加胃肠道动力，减少地高辛的吸收。阿卡波糖还可能干扰地高辛吸收前的水解，从而改变相应基质的释放，从而影响地高辛实验室测试的可靠性。这些病例报告表明，地高辛的吸收被阿卡波糖的给药减少。...

... A possible interaction between digoxin and acarbose was reported. In these reports, absorption of digoxin was decreased dramatically by coadministration of acarbose. The hypoglycemic action of acarbose stems from the reversible and competitive inhibition of alpha-glucosidase that hydrolyzes oligosaccharides absorbed later as glucose molecules. Acarbose functions exclusively in intestine, and most of it appears unchanged in feces. Digoxin is a well-known medication used in the treatment of heart failure and/or chronic atrial fibrillation. Acarbose delays the digestion of sucrose and starch in humans; as a result, a disturbance of gastrointestinal transit, causing loose stools, follows. Therefore, it is possible that gastrointestinal motility is increased, and absorption of digoxin decreased, by coadministration with acarbose. It is also possible that acarbose interferes with the hydrolysis of digoxin before its absorption, resulting in alteration in the release of the corresponding genine and thus affecting the reliability of the digoxin laboratory test. These case reports indicate that the absorption of digoxin is decreased by the administration of acarbose. ...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在一项单中心、安慰剂对照的临床研究中，测试了含有氢氧化镁和氢氧化铝的抗酸剂（Maalox 70；10毫升）对口服降糖药阿卡波糖（Glucobay 100，Bay g 5421，CAS 56180；100毫克）药效动力学的影响，研究对象为24名健康男性志愿者。药物单独使用或联合使用，并与安慰剂进行比较。志愿者被随机分配到四个不同的治疗组。连续4天的每日用药为1片安慰剂片，或1片含100毫克阿卡波糖的片剂，或1片含100毫克阿卡波糖加10毫升抗酸剂悬浮液，或1片安慰剂片加10毫升抗酸剂悬浮液，治疗之间有6-10天的清洗期。疗效评估基于服用75克蔗糖后餐后血糖和血清胰岛素水平，测量最大浓度和“曲线下面积”（0-4小时）。未检测到抗酸剂对阿卡波糖降低血糖和胰岛素作用的影响。因此，阿卡波糖与所测试的抗酸剂之间似乎没有显著相互作用。与所测试的抗酸剂类似的抗酸剂在与阿卡波糖联合使用时不需要被归类为禁忌。

In a single-centre, placebo-controlled, clinical study, the influence of an antacid containing magnesium hydroxide and aluminium hydroxide (Maalox 70; 10 mL) on the pharmacodynamics of the oral antidiabetic drug acarbose (Glucobay 100, Bay g 5421, CAS 56180; 100 mg) was tested in 24 healthy male volunteers. The drugs were given alone or in combination and were compared with placebo. Volunteers were randomized into four different treatment groups. The daily medication over 4 days was 1 x 1 placebo tablet, or 1 x 1 tablet containing 100 mg acarbose, or 1 x 1 tablet containing 100 mg acarbose plus 10 mL antacid suspension, or 1 x 1 placebo tablet plus 10 ml antacid suspension, interrupted by wash-out phases of 6-10 days between successive treatments. Efficacy was assessed on the basis of postprandial blood glucose and serum insulin levels after administration of 75 g sucrose, and was measured as maximal concentrations and 'area under the curve' (0-4 hr). No influence of the antacid on the blood glucose and insulin-lowering effect of acarbose could be detected. Hence, there does not appear to be a significant interaction between acarbose and the antacid tested. Antacids similar to that tested do not need to be classified as a contraindication when used in combination with acarbose.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

为了探究阿卡波糖治疗是否改变共同给药的罗格列酮的药代动力学（PK）。十六名健康志愿者（24-59岁）在第1天接受了单次8毫克的罗格列酮剂量，随后在接下来的7天中重复给予阿卡波糖[100毫克，每日三次（随餐）]。在阿卡波糖每日三次给药的最后一天（第8天），将单次剂量的罗格列酮与阿卡波糖的早晨剂量一起给予。比较了第1天和第8天罗格列酮给药后的PK曲线，并计算了点估计（PE）和相关95%置信区间（CI）。罗格列酮的吸收（以峰浓度Cmax和达峰时间Tmax衡量）不受阿卡波糖的影响。从时间零到无穷大的浓度-时间曲线下面积[AUC(0-∞)]在罗格列酮和阿卡波糖联合给药时平均降低了12%（95% CI -21%, -2%），并伴随着终末消除半衰期大约减少了1小时（23%）（4.9小时对比3.8小时）。这种AUC(0-∞)的小幅减少似乎是由于罗格列酮的系统清除率改变，而不是吸收的变化。观察到的AUC(0-∞)和半衰期的变化不太可能具有临床意义。罗格列酮和阿卡波糖的联合给药耐受性良好。以治疗剂量给予的阿卡波糖对罗格列酮的药代动力学有轻微但临床上不显著的影响。

To investigate whether treatment with acarbose alters the pharmacokinetics (PK) of coadministered rosiglitazone. Sixteen healthy volunteers (24-59-years old) received a single 8-mg dose of rosiglitazone on day 1, followed by 7 days of repeat dosing with acarbose [100 mg three times daily (t.i.d.) with meals]. On the last day of acarbose t.i.d. dosing (day 8), a single dose of rosiglitazone was given with the morning dose of acarbose. PK profiles following rosiglitazone dosing on days 1 and 8 were compared, and point estimates (PE) and associated 95% confidence intervals (CI) were calculated. Rosiglitazone absorption [as measured with peak plasma concentration (Cmax) and time to peak concentration (Tmax)] was unaffected by acarbose. The area under the concentration-time curve from time zero to infinity [AUC(0-infinity)] was on average 12% lower (95% CI-21%, -2%) during rosiglitazone + acarbose coadministration and was accompanied by an approximate 1-hr (23%) reduction in terminal elimination half-life (4.9 hr versus 3.8 hr). This small decrease in AUC(0-infinity) appears to be due to an alteration in systemic clearance of rosiglitazone and not changes in absorption. These observed changes in AUC(0-infinity) and half-life are not likely to be clinically relevant. Coadministration of rosiglitazone and acarbose was well tolerated. Acarbose administered at therapeutic doses has a small, but clinically insignificant, effect on rosiglitazone pharmacokinetics.

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和。如果患者停止呼吸，请开始人工呼吸，最好使用需求阀复苏器、球囊阀面罩设备或口袋面罩，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。如果患者呕吐，让患者身体前倾或将其置于左侧（如果可能，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。寻求医疗救助。 /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)

吸收、分配和排泄

在一项针对6名健康男性的研究中，口服阿卡波糖的剂量中不到2%被吸收为活性药物，而大约35%的总放射性来自14C标记口服剂量被吸收。平均来看，口服剂量的51%在摄入后96小时内以未吸收的药物相关放射性物质形式从粪便中排出。因为阿卡波糖在胃肠道的局部作用，这种母体化合物的低系统生物利用度在治疗上是期望的。

In a study of 6 healthy men, less than 2% of an oral dose of acarbose was absorbed as active drug, while approximately 35% of total radioactivity from a 14C-labeled oral dose was absorbed. An average of 51% of an oral dose was excreted in the feces as unabsorbed drug-related radioactivity within 96 hours of ingestion. Because acarbose acts locally within the gastrointestinal tract, this low systemic bioavailability of parent compound is therapeutically desired.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在健康志愿者口服14C标记的阿卡波糖后，放射性物质的血浆峰浓度在给药后14-24小时达到，而活性药物的血浆峰浓度大约在1小时时达到。阿卡波糖相关放射性物质的吸收延迟反映了由肠道细菌或肠道酶水解可能形成的代谢物的吸收。

Following oral dosing of healthy volunteers with 14C-labeled acarbose, peak plasma concentrations of radioactivity were attained 14-24 hours after dosing, while peak plasma concentrations of active drug were attained at approximately 1 hour. The delayed absorption of acarbose-related radioactivity reflects the absorption of metabolites that may be formed by either intestinal bacteria or intestinal enzymatic hydrolysis.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

阿卡波糖在小肠中代谢，主要由肠道细菌和消化酶完成。其中一部分代谢物（约34%的剂量）被吸收并随后通过尿液排出。

Acarbose is metabolized exclusively within the gastrointestinal tract, principally by intestinal bacteria, but also by digestive enzymes. A fraction of these metabolites (approximately 34% of the dose) was absorbed and subsequently excreted in the urine.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

阿卡波糖被吸收作为完整药物的比例几乎完全由肾脏排泄。当阿卡波糖静脉给药时，在48小时内，有89%的剂量以活性药物的形式在尿液中回收。相比之下，口服剂量的不到2%以活性（即母化合物和活性代谢物）药物的形式在尿液中回收。这与母药的低生物利用度一致。

The fraction of acarbose that is absorbed as intact drug is almost completely excreted by the kidneys. When acarbose was given intravenously, 89% of the dose was recovered in the urine as active drug within 48 hours. In contrast, less than 2% of an oral dose was recovered in the urine as active (i.e., parent compound and active metabolite) drug. This is consistent with the low bioavailability of the parent drug.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 安全说明：
  S24/25
• WGK Germany：
  1
• 海关编码：
  29400090
• 危险品运输编号：
  NONH for all modes of transport
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H315,H319,H335

制备方法与用途

阿卡波糖简介

阿卡波糖（Acarbose）是一种C7N-氨基环醇类的假性四糖物质，通过与α-葡萄糖苷酶发生竞争性抑制作用而广泛应用于Ⅱ型糖尿病的治疗。它能够有效降低餐后高血糖。

临床应用

阿卡波糖是从放线菌培养液中分离得到的一种复杂低聚糖，是临床上常用的一线口服降糖药。其主要通过与肠黏膜α-葡萄糖苷酶结合，抑制该酶的活性，从而减缓食物中淀粉、蔗糖、乳糖、麦芽糖、糊精等碳水化合物的降解速度。这延缓了葡萄糖的吸收，达到降低餐后血糖的目的，并间接改善空腹血糖水平，减轻尿糖现象。此外，阿卡波糖还能减轻体重、降低血压和甘油三酯水平，长期服用可降低心血管疾病的风险，适用于以碳水化合物为主要食物成分或餐后血糖升高的2型糖尿病患者。

副反应

常见胃肠道功能紊乱症状，包括腹胀、腹泻和腹痛。这些症状是由于糖类在小肠内分解及吸收障碍，在结肠内由细菌作用于未被吸收的糖类而产生。罕见情况下，阿卡波糖可能会引起肝细胞性肝损伤，伴有黄疸和转氨酶升高，停药后可缓解。此外，过敏反应和皮肤反应也少见。

制备

阿卡波糖的生物合成途径可以概括为以下三个过程：

1. 氨基环醇的合成：7-P-景天庚糖逐步通过一系列酶促反应生成NDP-1-epi-valienol-7-phosphate。
2. 4-氨基-4,6-二脱氧葡萄糖的合成：D-1-磷酸葡萄糖经过核苷酸化、脱水和转氨基等步骤，最终生成dTDP-4-氨基-4,6-双脱氧葡萄糖。
3. 阿卡波糖的合成：NDP-1-epi-valienol-7-phosphate与dTDP-4-氨基-4,6-双脱氧葡萄糖在糖基转移酶的作用下发生糖基转移反应，生成dTDP-acarvicose-7-phosphate。随后，dTDP-acarvicose-7-phosphate再与麦芽糖分子结合，生成acarbose-7-phosphate。菌体在胞内完成acarbose-7-phosphate的合成后，还需通过转运蛋白AcbWXY/GacWXY将该物质跨膜转运至胞外，并发生去磷酸化作用最终生成阿卡波糖。

化学性质

无定形粉末。 [α]D18 +165°（C=0.4，水）。

用途

阿卡波糖是一种低聚糖，可逆地抑制小肠粘膜刷状缘上的α-糖苷酶活性，缓慢降低消化复杂多糖及蔗糖的速度，从而延缓葡萄糖的吸收。它常用于胰岛素依赖型和非胰岛素依赖型糖尿病的治疗。

类别与毒性

类别：有毒物品
毒性分级：低毒
急性毒性：口服-大鼠 LD50: 24000 毫克/公斤；口服 - 小鼠 LD50: 24000 毫克/公斤
可燃性危险特性：可燃；加热分解释放有毒氮氧化物烟雾。
储运特性：库房通风低温干燥。
灭火剂：干粉、泡沫、砂土和水。

文献信息

• COMPOSITIONS AND METHODS FOR COMBINATORIAL DRUG DISCOVERY IN NANOLITER DROPLETS
  申请人：The Broad Institute, Inc.

  公开号：US20200353033A1

  公开（公告）日：2020-11-12

  The present disclosure relates compositions and methods for combinatorial drug discovery in nanoliter droplets. More particularly, the disclosure relates to novel synergistic agents that increase efficacy of antibiotic agents to treat bacterial infection.