acarbose | 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: acarbose
• 英文别名: 4'',6''-dideoxy-4''-<(1S)-(1,4,6/5)-4,5,6-trihydroxy-3-hydroxymethyl-2-cyclohexenylamino>maltotriose (acarbose)；glucobay；4,6-dioxy-4-{[4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-en-1-yl]amino}hexyopyranosyl-1-4-hexopyranosyl-4-hexopyranose；4,6-dioxy-4{[4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-en-1-yl]amino}hexyopyranosyl-1-4-hexopyranosyl-4-hexopyranose；(3R,4R,5S,6R)-5-[(2R,3R,4R,5S,6R)-5-[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-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；68107-33-5；106864-09-9
• 化学式: C₂₅H₄₃NO₁₈
• mdl: MFCD06407598
• 分子量: 645.612
• InChiKey: XUFXOAAUWZOOIT-UGEKTDRHSA-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
• 碰撞截面：
  231 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)：
  -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水平升高，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赞助商。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发现由阿卡波糖引起的病例。在几个实例中进行了再挑战，并导致发病时间缩短。

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

• 药物性肝损伤

化合物：阿卡波糖

Compound:acarbose

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：最令人关注的药物性肝损伤

DILI Annotation:Most-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重等级：8

Severity Grade:8

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：警告和预防措施

Label Section:Warnings and precautions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

在一项针对6名健康男性的研究中，服用阿卡波糖的口服剂量中，不到2%被吸收为活性药物，而大约35%的总放射性来自14C标记的口服剂量被吸收。平均来说，51%的口服剂量在摄入后96小时内以未吸收的药物相关放射性物质形式随粪便排出。因为阿卡波糖在胃肠道内局部作用，这种亲本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，放射性物质的血浆浓度峰值在给药后14-24小时达到，而活性药物的血浆浓度峰值在大约1小时达到。阿卡波糖相关放射性物质的延迟吸收反映了由肠道细菌或肠道酶水解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