2-[(4R,6S,7R,9R,10R,11E,13E,16R)-6-[5-(4,5-dihydroxy-4,6-dimethyloxan-2-yl)oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-10-[5-(dimethylamino)-6-methyloxan-2-yl]oxy-4-hydroxy-5-methoxy-9,16-dimethyl-2-oxo-1-oxacyclohexadeca-11,13-dien-7-yl]acetaldehyde | 8025-81-8

• 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: 2-[(4R,6S,7R,9R,10R,11E,13E,16R)-6-[5-(4,5-dihydroxy-4,6-dimethyloxan-2-yl)oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-10-[5-(dimethylamino)-6-methyloxan-2-yl]oxy-4-hydroxy-5-methoxy-9,16-dimethyl-2-oxo-1-oxacyclohexadeca-11,13-dien-7-yl]acetaldehyde
• CAS: 8025-81-8
• 化学式: C₄₃H₇₄N₂O₁₄
• 分子量: 843.1
• InChiKey: ACTOXUHEUCPTEW-BWAMRQHNSA-N

物化性质

• 熔点：
  126-128 °C
• 沸点：
  914℃
• 比旋光度：
  D20 -80° (methanol)
• 闪点：
  >110°(230°F)
• 溶解度：
  乙醇：50 mg/mL，清澈至微浑浊，淡黄色
• 颜色/状态：
  Amorphous
• 蒸汽压力：
  9.9X10-31 mm Hg at 25 °C (est)
• 旋光度：
  Specific optical rotation: -80 deg at 20 °C/D
• 分解：
  When heated to decomposition it emits acrid smoke & irritating fumes.
• 解离常数：
  pKa1 = 7.88; pKa2 = 9.28 (est)

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  59
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  195
• 氢给体数：
  4
• 氢受体数：
  16

ADMET

代谢

在牛体内，形成了新大环内酯类药物的代谢物——去甲基金霉素。在给药后14-28天，肌肉和肾脏中金霉素的浓度略高于螺旋霉素；在肌肉中，去甲基金霉素和螺旋霉素的水平大约相等。

In cattle, the metabolite neospiramycin, the demycarosyl derivative, is formed. Concentrations of neospiramycin in muscle and kidney were marginally higher than those of spiramycin 14-28 days after dosing; in muscle, levels of neospiramycin and spiramycin were approximately equal.

来源:Hazardous Substances Data Bank (HSDB)

代谢

spiramycin在肝脏中被代谢成活性代谢物；大量通过胆汁排出，约10%通过尿液排出。

Spiramycin is metabolized in the liver to active metabolites; substantial amounts are excreted in the bile and about 10% in the urine.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

大环内酯类抗生素包括天然成员、前药和半合成衍生物。这些药物适用于多种感染，并且常常与其他药物疗法联合使用，因此存在潜在的药代动力学相互作用。大环内酯类可以通过在肝脏形成复合物并使微粒体药物氧化酶失活来抑制药物代谢，同时通过其抗生素效果干扰肠内微生物群。在过去的20年中，有多份报告指出大环内酯类是临床严重药物相互作用的潜在来源。然而，不同的大环内酯类在这方面存在差异，并非所有的大环内酯类都会引起药物相互作用。随着许多半合成大环内酯类抗生素的近期出现，现在很明显，它们可能被分为三类，以引起药物相互作用。第一组（例如酮内酯、红霉素）是那些容易形成亚硝基烷烃并与细胞色素P450代谢物形成无活性复合物的药物。第二组（例如交沙霉素、氟红霉素、罗红霉素、克拉霉素、米卡霉素和米地霉素）形成复合物的程度较小，很少产生药物相互作用。最后一组（例如螺旋霉素、罗吉霉素、地红霉素和阿奇霉素）不使细胞色素P450失活，无法改变其他化合物的药代动力学。似乎有两个结构因素对于大环内酯类抗生素导致细胞色素P450的诱导以及在体内或体外形成抑制性细胞色素P450-铁-亚硝基烷烃代谢物复合物非常重要：大环内酯分子中存在一个非阻碍性的、易于接近的N-二甲氨基团以及药物的疏水性特征。酮内酯是微粒体肝酶的最强抑制剂，导致甲基强的松龙、茶碱、卡马西平、非那宗（安替比林）和三唑仑的代谢显著减少。酮内酯可能导致服用麦角生物碱的患者出现麦角病，以及那些服用口服避孕药的患者出现胆汁淤积性黄疸。红霉素及其不同的前药似乎是对药物代谢的较不强烈抑制剂。然而，病例报告和控制研究已经表明，红霉素可能会与茶碱、卡马西平、甲基强的松龙、华法林、环孢素、三唑仑、咪达唑仑、阿芬太尼、双异丙吡胺和溴隐亭相互作用，降低药物清除率。红霉素似乎也能增加那些排泄大量还原型地高辛代谢物患者的地高辛的生物利用度，这可能是由于破坏了负责形成这些化合物的肠内菌群。这些有争议的大环内酯类抗生素不应与其他已知受其代谢影响的药物同时使用，或者在非常小心的情况下，只有在仔细监测患者的情况下才联合使用。

The macrolide antibiotics include natural members, prodrugs & semisynthetic derivatives. These drugs are indicated in a variety of infections & are often combined with other drug therapies, thus creating the potential for pharmacokinetic interactions. Macrolides can both inhibit drug metab in the liver by complex formation & inactivation of microsomal drug oxidising enzymes & also interfere with microorganisms of the enteric flora through their antibiotic effects. Over the past 20 yrs, a number of reports have incriminated macrolides as a potential source of clinically severe drug interactions. However, differences have been found between the various macrolides in this regard & not all macrolides are responsible for drug interactions. With the recent advent of many semisynthetic macrolide antibiotics it is now evident that they may be classified into 3 different groups in causing drug interactions. The first group (e.g. troleandomycin, erythromycins) are those prone to forming nitrosoalkanes & the consequent formation of inactive cytochrome P450-metabolite complexes. The second group (e.g. josamycin, flurithromycin, roxithromycin, clarithromycin, miocamycin & midecamycin) form complexes to a lesser extent & rarely produce drug interactions. The last group (e.g. spiramycin, rokitamycin, dirithromycin & azithromycin) do not inactivate cytochrome P450 & are unable to modify the pharmacokinetics of other cmpds. It appears that 2 structural factors are important for a macrolide antibiotic to lead to the induction of cytochrome P450 & the formation in vivo or in vitro of an inhibitory cytochrome P450-iron-nitrosoalkane metabolite complex: the presence in the macrolide molecules of a non-hindered readily accessible N-dimethylamino group & the hydrophobic character of the drug. Troleandomycin ranks first as a potent inhibitor of microsomal liver enzymes, causing a significant decr of the metab of methylprednisolone, theophylline, carbamazepine, phenazone (antipyrine) & triazolam. Troleandomycin can cause ergotism in patients receiving ergot alkaloids & cholestatic jaundice in those taking oral contraceptives. Erythromycin & its different prodrugs appear to be less potent inhibitors of drug metab. Case reports & controlled studies have, however, shown that erythromycins may interact with theophylline, carbamazepine, methylprednisolone, warfarin, cyclosporin, triazolam, midazolam, alfentanil, disopyramide & bromocriptine, decreasing drug clearance. The bioavailability of digoxin appears also to be increased by erythromycin in patients excreting high amounts of reduced digoxin metabolites, probably due to destruction of enteric flora responsible for the formation of these cmpds. These incriminated macrolide antibiotics should not be administered concomitantly with other drugs known to be affected metabolically by them, or at the very least, combined admin should be carried out only with careful patient monitoring.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

已报告在给予螺旋霉素时，左旋多巴的血浆浓度降低。

Reduced plasma concentrations of levodopa have been reported when given with spiramycin.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

作者报告了一位21岁女性的病例，她患有先天性长QT综合症，经历了多次晕厥发作，至少有一次是由扭转性室性心动过速引起的。这种突然的并发症归因于48小时内同时开具了螺旋霉素和美喹他嗪。尽管这两种药物属于可能触发这种心律失常的药物家族，但它们并不被认为是扭转性室性心动过速的易感因素。撤除这种治疗导致晕厥发作完全消退，随访两年，最初的QTc间期显著缩短，尽管仍然比正常时间长。这个病例强调了这两种药物家族联合用药的潜在风险，尤其是在患有先天性长QT综合症的患者中。

The authors report the case of a 21 year old woman with a congenital long QT syndrome who had several syncopal attacks at least one of which was caused by torsades de pointes. This sudden complication was attributed to the simultaneous prescription of Spiramycine and Mequitazine over a 48 hour period. These two drugs are not considered to be predisposing factors for torsades de pointes despite the fact that they belong to two families of drugs which can trigger this type of arrhythmia. The withdrawal of this treatment led to the complete regression of the syncopal episodes with a follow-up of two years and a significant shortening of the initial QTc interval which remained, nevertheless, longer than normal. This case underlines the potential risks of drug associations of these two families of drugs, especially in patients with the congenital long QT syndrome.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：螺旋霉素是一种大环内酯类抗生素，用于治疗和控制动物中多种细菌和支原体感染。它以螺旋霉素磷酸盐的形式用于动物饲料，并作为更易溶的螺旋霉素酯形式通过其他途径给药。它还被用于治疗原虫感染，如隐孢子虫病和弓形虫病。人类暴露和毒性：据报道，螺旋霉素在职业环境中会引起接触性皮炎。一名在饲料厂工作的男子由于空气中的螺旋霉素而患上了过敏性接触性皮炎。患者在工作期间裸露区