(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-tetrahydropyran-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one | 122463-26-7

• 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: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-tetrahydropyran-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one
• 英文别名: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-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: 122463-26-7；83905-01-5
• 化学式: C₃₈H₇₂N₂O₁₂
• 分子量: 749.0
• InChiKey: MQTOSJVFKKJCRP-VAROOZCXSA-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)
• 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。已经鉴定出多达10种阿奇霉素的代谢物，所有这些代谢物在微生物学上都是不活跃的。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会发生。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

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：由于阿奇霉素在母乳中的含量较低，且在婴儿中较高剂量使用，预计不会对哺乳婴儿造成不良影响。监测婴儿可能出现对胃肠道菌群的影响，如呕吐、腹泻、念珠菌病（鹅口疮、尿布疹）。未经证实的流行病学证据表明，在母乳喂养的前两周内，母亲使用大环内酯类抗生素可能会增加婴儿肥厚性幽门狭窄的风险，但其他人对此关系提出了质疑。在一项研究中，给分娩时携带致病性葡萄球菌和链球菌的女性单次剂量的阿奇霉素，减少了母乳中这些细菌的数量，但增加了母乳中阿奇霉素耐药性大肠杆菌和肺炎克雷伯菌的流行率。 ◉ 对哺乳婴儿的影响：一项对被诊断患有婴儿肥厚性幽门狭窄的婴儿的队列研究发现，受影响的婴儿在分娩后90天内母亲使用大环内酯类抗生素的可能性是正常婴儿的2.3至3倍。对婴儿进行分层发现，女性婴儿的比值比为10，男性婴儿为2。所有受影响婴儿的母亲都哺乳了他们的婴儿。大多数大环内酯类药物的处方是红霉素，但只有7%是阿奇霉素。然而，作者没有说明受影响婴儿的母亲使用了哪种大环内酯类药物。 一项在丹麦进行的15年数据回顾性数据库研究发现，在分娩后前13天内使用大环内酯类药物的母亲所生的婴儿患婴儿肥厚性幽门狭窄的风险增加了3.5倍，但后来暴露并没有增加风险。婴儿中哺乳的比例未知，但可能很高。使用每种大环内酯类药物的妇女比例也没有报告。 一项比较了母亲使用阿莫西林和服用大环内酯类抗生素的哺乳婴儿的研究发现，没有肥厚性幽门狭窄的实例。然而，大多数在母乳中暴露于大环内酯类的婴儿暴露于罗西霉素。在55名暴露于大环内酯类的婴儿中，只有10名暴露于阿奇霉素。暴露于大环内酯类的婴儿中有12.7%出现了不良反应，这与暴露于阿莫西林婴儿的发生率相似。反应包括皮疹、腹泻、食欲不振和嗜睡。 8名妇女在剖宫产手术前15、30或60分钟静脉注射500毫克阿奇霉素，然后哺乳他们的新生儿。他们的婴儿没有出现不良反应。 两项荟萃分析未能证明母亲在哺乳期间使用大环内酯类药物与婴儿肥厚性幽门狭窄之间的关系。 ◉ 对泌乳和母乳的影响：在冈比亚进行的一项双盲对照研究中，给携带金黄色葡萄球菌、肺炎链球菌或B组链球菌的鼻咽部携带者妇女在分娩时单次给予2克剂量的阿奇霉素。接受阿奇霉素的妇女的乳汁样本中携带这些微生物的比例为9.6%，而接受安慰剂的妇女为21.9%。分娩后第6天，母亲和婴儿的鼻咽部携带率也有所降低。然而，后来的分析发现，口服分娩时阿奇霉素并没有减少大肠杆菌和肺炎克雷伯菌的携带，并且与母乳中阿奇霉素耐药性大肠杆菌和肺炎克雷伯菌分离株的增加有关。

◉ Summary of Use during Lactation:Because of the low levels of azithromycin in breastmilk and use in infants in higher doses, it would not be expected to cause adverse effects in breastfed infants. Monitor the infant for possible effects on the gastrointestinal flora, such as vomiting, diarrhea, candidiasis (thrush, diaper rash). Unconfirmed epidemiologic evidence indicates that the risk of infantile hypertrophic pyloric stenosis might be increased by maternal use of macrolide antibiotics during the first two weeks of breastfeeding, but others have questioned this relationship. In one study, a single dose of azithromycin given during labor to women who were nasal carriers of pathogenic Staphylococcus and Streptococcus reduced the counts of these bacteria in breastmilk, but increased the prevalence of azithromycin-resistant E. coli and K. pneumoniae in breastmilk. ◉ Effects in Breastfed Infants:A cohort study of infants diagnosed with infantile hypertrophic pyloric stenosis found that affected infants were 2.3 to 3 times more likely to have a mother taking a macrolide antibiotic during the 90 days after delivery. Stratification of the infants found the odds ratio to be 10 for female infants and 2 for male infants. All of the mothers of affected infants nursed their infants. Most of the macrolide prescriptions were for erythromycin, but only 7% were for azithromycin. However, the authors did not state which macrolide was taken by the mothers of the affected infants. A retrospective database study in Denmark of 15 years of data found a 3.5-fold increased risk of infantile hypertrophic pyloric stenosis in the infants of mothers who took a macrolide during the first 13 days postpartum, but not with later exposure. The proportion of infants who were breastfed was not known, but probably high. The proportion of women who took each macrolide was also not reported. A study comparing the breastfed infants of mothers taking amoxicillin to those taking a macrolide antibiotic found no instances of pyloric stenosis. However, most of the infants exposed to a macrolide in breastmilk were exposed to roxithromycin. Only 10 of the 55 infants exposed to a macrolide were exposed to azithromycin. Adverse reactions occurred in 12.7% of the infants exposed to macrolides which was similar to the rate in amoxicillin-exposed infants. Reactions included rash, diarrhea, loss of appetite, and somnolence. Eight women who were given azithromycin 500 mg intravenously 15, 30 or 60 minutes prior to incision for cesarean section breastfed their newborn infants. No adverse events were noted in their infants. Two meta-analyses failed to demonstrate a relationship between maternal macrolide use during breastfeeding and infantile hypertrophic pyloric stenosis. ◉ Effects on Lactation and Breastmilk:In a double-blind, controlled study in Gambia, women who were nasopharyngeal carriers of Staphylococcus aureus, Streptococcus pneumoniae or group B streptococcus were given a single 2 gram dose of azithromycin during labor. Milk samples from women who received azithromycin had 9.6% prevalence of carriage of the organisms compared to 21.9% in women who received placebo. Nasopharyngeal carriage in mothers and infants was also reduced on day 6 postpartum. However, a later analysis found oral intrapartum azithromycin did not reduce carriage of Escherichia coli and Klebsiella pneumoniae and was associated with an increase in the prevalence of azithromycin-resistant E. coli and K. pneumoniae isolates in breastmilk.

来源:Drugs and Lactation Database (LactMed)

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）会增加匹莫齐特的浓度，并且与QT间期延长和严重心血管反应的风险相关，所以匹莫齐特的生产商指出，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

尽管尚未对阿奇霉素进行特定的药物相互作用研究，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，应仔细监测患者。

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

尽管单剂量缓释口服悬浮剂型阿奇霉素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（片剂或口服悬浮剂）不应与含铝或镁的抗酸剂同时服用。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服用口服阿奇霉素500毫克会降低阿奇霉素的吸收速率，表现为峰值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

尽管尚未对阿奇霉素进行特定的药物相互作用研究，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、二氢麦角胺）浓度升高。因此，如果阿奇霉素与麦角生物碱同时使用，应仔细监测患者。

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)

吸收、分配和排泄

胆汁排泄的阿奇霉素，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会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进入相对酸性的溶酶体，作为铁捕获的结果，以及与核苷转运系统相关的能量依赖途径。

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迅速分布，并且细胞内浓度高，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，组织与血浆的比例会增加。

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)

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。

文献信息

• Ester Linked Macrolides Useful For The Treatment of Microbial Infections
  申请人：Alihodzic Sulejman

  公开号：US20080255060A1

  公开（公告）日：2008-10-16

  The present invention relates to 14- or 15-membered macrolides substituted at the 4″ position of formula (I) and pharmaceutically acceptable derivatives thereof, to processes for their preparation and their use in therapy or prophylaxis of systemic or topical microbial infections in a human or animal body.

  本发明涉及在式(I)的4"位置取代的14或15元大环内酯及其药学上可接受的衍生物，以及它们的制备方法和在人或动物体内治疗或预防系统性或局部微生物感染的用途。