(2S,3R,4S,5S,8S,10S,11S,12R,13R,14S)-11-[(2R,3S,4R,6S)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2S,4S,5R,6R)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one | 83905-01-5

• 物质功能分类: 原料药 - 抗生素类药物 - 大环内酯类药
• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (2S,3R,4S,5S,8S,10S,11S,12R,13R,14S)-11-[(2R,3S,4R,6S)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2S,4S,5R,6R)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one
• CAS: 83905-01-5
• 化学式: C₃₈H₇₂N₂O₁₂
• 分子量: 749.0
• InChiKey: MQTOSJVFKKJCRP-SAEDAXQJSA-N

物化性质

• 熔点：
  113-115°C
• 比旋光度：
  D20 -37° (c = 1 in CHCl3)
• 沸点：
  822.1±65.0 °C(Predicted)
• 密度：
  1.18±0.1 g/cm3(Predicted)
• 溶解度：
  几乎不溶于水，易溶于无水乙醇和二氯甲烷。
• 颜色/状态：
  Amorphous solid
• 蒸汽压力：
  2.65X10-24 mm Hg at 25 °C (est)
• 亨利常数：
  Henry's Law constant = 5.3X10-29 atm-cu m/mol at 25 °C (est)
• 旋光度：
  Specific optical rotation: -37 °C at 20 °C/D (c = 1 on CHCl3)
• 解离常数：
  pKa = 8.74

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  52
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.97
• 拓扑面积：
  180
• 氢给体数：
  5
• 氢受体数：
  14

ADMET

代谢

生物转化的主要途径涉及去氧糖或大环内酯环9a位置上的N-脱甲基化。其他代谢途径包括克拉定糖和去氧糖部分以及大环内酯环的O-脱甲基化和水解和/或羟基化。已经鉴定出阿奇霉素的最多10种代谢物，所有这些代谢物在微生物学上均不活跃。尽管短期给予阿奇霉素会导致药物在肝脏中积累并增加阿奇霉素脱甲基酶活性，但目前证据表明，通过细胞色素-代谢物复合物形成导致肝脏细胞色素p450诱导失活的情况并不发生。与红霉素不同，阿奇霉素不会通过此途径抑制其自身的代谢。

The principal route of biotransformation involves N-demethylation of the desosamine sugar or at the 9a position on the macrolide ring. Other metabolic pathways include O-demethylation and hydrolysis and/or hydroxylation of the cladinose and desosamine sugar moieties and the macrolide ring. Up to 10 metabolites of azithromycin have been identified, and all are microbiologically inactive. While short-term administration of azithromycin produces hepatic accumulation of the drug and increases azithromycin demethylase activity, current evidence indicates that hepatic cytochrome p450 induction of inactivation via cytochrome-metabolite complex formation does not occur. In contrast to erythromycin, azithromycin does not inhibit its own metabolism via this pathway.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

因为同时使用匹莫齐特和其他大环内酯类药物（例如，克拉霉素）会增加匹莫齐特的血药浓度，并且与QT间期延长和严重心血管副作用的风险相关，匹莫齐特的制造商表示，匹莫齐特和大环内酯类药物（包括阿奇霉素）的同时使用是禁忌的。

Because concomitant use of pimozide and other macrolides (e.g., clarithromycin) has increased pimozide concentrations and is associated with a risk of prolonged QT interval and serious cardiovascular effects, the manufacturer of pimozide states that concomitant use of pimozide and macrolides (including azithromycin) is contraindicated.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

尽管尚未进行阿奇霉素与特定药物的相互作用研究，但与其他大环内酯类药物同时使用已导致苯妥英钠浓度升高。因此，如果阿奇霉素和苯妥英钠同时使用，应密切监测患者。

Although specific drug interaction studies have not been performed with azithromycin, concomitant use with other macrolides has resulted in increased phenytoin concentrations. Therefore, the patient should be carefully monitored if azithromycin and phenytoin are used concomitantly.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

尽管阿奇霉素的单剂量缓释口服悬浮液可以不考虑含有氢氧化镁和/或氢氧化铝的抗酸剂，但传统的口服阿奇霉素制剂（片剂或口服悬浮液）不应与含铝或镁的抗酸剂同时使用。一项使用阿奇霉素胶囊（目前已不再商业销售）的研究表明，与含铝和氢氧化镁的抗酸剂同时口服阿奇霉素500毫克，会导致阿奇霉素吸收速率降低，表现为峰血清阿奇霉素浓度降低了24％；然而，阿奇霉素的吸收程度（AUC）不受影响。

Although the single-dose extended-release oral suspension of azithromycin may be taken without regard to antacids containing magnesium hydroxide and/or aluminum hydroxide, conventional oral azithromycin preparations (tablets or oral suspension) should not be administered simultaneously with aluminum- or magnesium-containing antacids. A study using azithromycin capsules (no longer commercially available) indicate that administration of oral azithromycin 500 mg with an aluminum- and magnesium hydroxide-containing antacid resulted in a decreased rate of absorption of azithromycin as evidenced by 24% reduction in peak serum azithromycin concentrations; however, the extent of azithromycin absorption (AUC) was unaffected.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

尽管尚未进行阿奇霉素与特定药物的相互作用研究，但与其他大环内酯类药物同时使用已导致麦角生物碱（麦角胺、双氢麦角胺）浓度升高。因此，如果阿奇霉素与麦角生物碱同时使用，应密切监测患者。

Although specific drug interaction studies have not been performed with azithromycin, concomitant use with other macrolides has resulted in increased concentrations of ergot alkaloids (ergotamine, dihydroergotamine). Therefore, the patient should be carefully monitored if azithromycin and ergot alkaloids are used concomitantly.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

紧急和支持性措施：保持呼吸道通畅，必要时辅助呼吸。如果出现昏迷、惊厥、低血压、过敏反应和溶血，则进行治疗。用静脉晶体液替代由胃肠炎引起的液体损失。/抗菌药物/

Emergency and supportive measures: Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, anaphylaxis, and hemolysis if they occur. Replace fluid losses resulting from gastroenteritis with intravenous crystalloids. /Antibacterial agents/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

胆汁排泄阿奇霉素，主要是以未改变的药物形式，是口服给药后消除的主要途径。

Biliary excretion of azithromycin, predominantly as unchanged drug is a major route of elimination following oral administration.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

阿奇霉素在口服给药后从胃肠道迅速吸收；药物的吸收不完全，但超过了红霉素。据报道，阿奇霉素的绝对口服生物利用度大约为34-52%，单次剂量为500毫克至1.2克，以各种口服剂型给药。有限的证据表明，阿奇霉素的低生物利用度是由于不完全的胃肠道吸收，而不是药物的酸性降解或广泛的首过代谢。

Azithromycin is rapidly absorbed from the GI tract after oral administration; absorption of the drug is incomplete but exceeds that of erythromycin. The absolute oral bioavailability of azithromycin is reported to be approximately 34-52% with single doses of 500 mg to 1.2 g administered as various oral dosage forms. Limited evidence indicates that the low bioavailability of zithromycin results from incomplete GI absorption rather acid degradation of the drug or extensive first-pss metabolism.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

阿奇霉素在口服或静脉注射后似乎能分布到大多数身体组织和体液中。阿奇霉素广泛的组织摄取归因于这种碱性抗生素被相对酸性的溶酶体通过铁捕获和与核苷转运系统相关的能量依赖途径所细胞摄取。

Azithromycin appears to be distributed into most body tissues and fluids after oral or IV administration. The extensive tissue uptake of azithromycin has been attributed to cellular uptake of this basic antibiotic into relatively acidic lysosomes as a result of iron trapping and to an energy-dependent pathway associated with the nucleoside transport system.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

由于阿奇霉素在组织中的快速分布和高细胞内浓度，通常在单次给药后，药物的组织浓度超过血浆浓度10到100倍；多次给药后，组织与血浆的比例增加。

Because of rapid distribution into tissues and high intracellular concentrations of azithromycin, tissue concentrations of the drug generally exceed plasma concentrations by 10- to 100-fold following single dose administration; with multiple dosing, the tissue-to-plasma ratio increases.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xi
• 安全说明：
  S22,S36/37,S45
• 危险类别码：
  R42/43
• WGK Germany：
  2
• 海关编码：
  2941500000
• 危险品运输编号：
  NONH for all modes of transport
• RTECS号：
  RN6960000

制备方法与用途

这段文本包含了关于阿奇霉素的详细信息,包括化学性质、用途和生产方法。主要要点如下:

1. 化学性质:

• 白色结晶
• 熔点113--115℃
• [α]D20 -37°(C=1，氯仿)

2. 用途:

• 抗生素类药物,用于治疗敏感细菌引起的各种感染
• 主要用于呼吸道感染、皮肤软组织感染和性传播疾病
• 对革兰阳性菌的抗菌活性更强,对革兰阴性菌如流感嗜血杆菌等也有一定作用

3. 生产方法: 以红霉素A为原料,经肟化后在盐酸作用下进行Beckmann重排,再脱水、还原、甲基化可得阿奇霉素。

4. 临床评价:

• 治疗呼吸道感染、泌尿生殖系统感染等效果良好
• 对心血管高风险人群可能增加心血管死亡风险,但在真实世界人群中缺乏研究

5. 药物使用注意事项:

• 需饭前1小时或饭后2小时服用
• 有变态反应立即停药并采取相应措施
• 定期随访肝功能

6. 真实世界研究结果: 阿奇霉素与未使用抗生素人群相比,心血管死亡风险显著增加,但不影响年轻人和中老年患者

这段信息详细介绍了阿奇霉素的化学性质、用途、生产方法以及临床应用情况。